Melanocortin receptor-specific compounds

ABSTRACT

A melanocortin receptor-specific compound of the general formula of structure I:  
                 
 
     where X, R 1 , R 2a , R 2b , R 3 , R 4a , R 4b , R 5a  and R 5b  are as defined in the specification, which compound binds with high affinity to one or more melanocortin receptors and is optionally an agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist, and may be employed for treatment of one or melanocortin receptor-associated conditions or disorders, and methods for the use of the compounds of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the filing of U.S.Provisional Patent Application Ser. No. 60/546,393, entitled“Melanocortin Receptor-Specific Tetra-Substituted piperazine Compounds”,filed on Feb. 19, 2004; and of U.S. Provisional Patent Application Ser.No. 60/467,442, entitled “Tetra-, Penta- and Hexa-Substituted piperazineCompounds and Derivatives”, filed on May 1, 2003; and the specificationof each thereof is incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention (Technical Field):

[0003] The present invention relates to tetra- and penta-substitutedpiperazine and piperazine-derivative ring compounds, the ring compoundsoptionally including one C═O or C═S member, that bind to one or moremelanocortin receptors and are optionally agonists, antagonists, mixedagonist-antagonists or inverse agonists with respect to one or moremelanocortin receptors, and use thereof for the treatment of metabolic,immune, infection-related and melanocortin receptor-mediated disorders.

[0004] 2. Description of Related Art

[0005] Note that the following discussion refers to a number ofpublications by author(s) and year of publication, and that due torecent publication dates certain publications are not to be consideredas prior art vis-a-vis the present invention. Discussion of suchpublications herein is given for more complete background and is not tobe construed as an admission that such publications are prior art forpatentability determination purposes.

[0006] Piperazines are an important class of molecular templates thathave been employed in the development of several drugs. However, in theprior art generally only mono- or di-substituted piperazine templateshave been employed. In a few instances a tri-substituted piperazine hasbeen employed, such as indinavir (Merck), an HIV protease inhibitor drugthat incorporates a tri-substituted piperazine.

[0007] Melanocortin Receptor-Specific Agents. A family of melanocortinreceptor types and subtypes have been identified, including melanocortin1 receptors (MC1-R) expressed on normal human melanocytes and melanomacells, melanocortin 2 receptors (MC2-R) for adrenocorticotropin (ACTH)expressed in cells of the adrenal gland, melanocortin 3 and melanocortin4 receptors (MC3-R and MC4-R), expressed primarily in cells in thehypothalamus, mid-brain and brainstem, and melanocortin 5 receptors(MC5-R), expressed in a wide distribution of tissues.

[0008] In general, compounds specific for MC1-R are believed to beuseful for treatment of melanoma. Compounds specific for MC3-R or MC4-Rare believed to be useful in regulation of energy homeostasis, includinguse as agents for attenuating food intake and body weight gain, for usein treatment of anorexia and cachexia, for treatment of obesity, andtreatment of other food intake and metabolism-related indications.Compounds specific for MC3-R and MC4-R, among other melanocortinreceptors, can further be used as agents for treatment of sexualdysfunction, including male erectile dysfunction. Other clinical usesare being explored, such as use of MC4-R antagonists as anxiolytic orantidepressant drugs. Other melanocortin receptor-specific compounds,such as MCR-1 agonists, can be used as tanning agents to increasemelanin production in the skin, acting as chemo-preventive agentsagainst harmful effects of UV solar radiation. Compounds specific forMCR-1 and MCR-3 may further be useful in regulation of inflammatoryprocesses. Compounds specific for MCR-5 may be used for treatment ofacne and related skin disorders due to over stimulation of sebaceousgland. Compounds specific for MCR-4 and MCR-5 may be used for treatmentof depression. Compounds specific for MCR-3 may find use as atherapeutic for treating salt-induced hypertension. In general, themelanocortin system is involved in diverse physiological functions,including energy balance, pigmentation, sexual function andinflammation.

[0009] The mechanism of action of compounds specific for MC3-R or MC4-Ras agents for attenuating food intake and body weight gain has not beenfully elucidated. While most reports suggest that MC4-R agonists may beemployed for attenuating food intake and body weight gain, it is clearthat agouti-related protein (AgRP), an endogenous inverse agonist, playsa critical role in the regulatory system. At least one group hassuggested that a neutral antagonist of AgRP may produce agonist-likeeffects in vivo. (Adan, R. A. H. and Kas, M. J. H. Inverse agonist gainsweight. TRENDS in Pharmacological Sciences 24(6):315-321, 2003.)However, no such compounds have heretofore been described. Further, allor virtually all MC4-R agonists compounds reported for attenuating foodintake or body weight gain in animal models have shown a “rebound”effect, with animals gaining weight equal to or, in most instances,exceeding controls on cessation of administration of the compounds.There is thus a need for compounds which attenuate food intake or bodyweight gain without causing a rebound effect on cessation ofadministration of the compound.

[0010] There is a significant need for compounds with high specificityfor discrete melanocortin receptors, as well as for compounds that areagonists, inverse agonists, antagonists, or otherwise bind to specificmelanocortin receptors. High affinity compounds for melanocortinreceptors can be used to exploit varied physiological responsesassociated with melanocortin receptors, as agonists, antagonists,inverse agonists or otherwise. In addition, melanocortin receptors havean effect on the activity of various cytokines, and high affinitycompounds for melanocortin receptors can be used to regulate cytokineactivity.

[0011] Piperazine Compounds. There are piperazine and piperidinecompounds known, such as those disclosed in WO 03/009850 (Amgen), WO03/009847 (Amgen), WO 03/094918 (Neurocrine Biosciences), WO 03/1093234(Procter & Gamble), WO 03/092690 (Procter & Gamble), WO 03/061660 (EliLilly and Company), WO 03/053927 (Taisho Pharm.), WO 03/031410(Neurocrine Biosciences), WO 03/007949 (Merck & Co.), WO 02/092566(Taisho Pharm.), WO 02/079146 (Bristol-Myers Squibb Company), WO02/070511 (Bristol-Myers Squibb Company), WO 02/068388 (Merck & Co.), WO02/068387 (Merck & Co.), WO 02/067869 (Merck & Co.), WO 02/059095 (EliLilly and Company), WO 02/00259 (Taisho Pharm.), and WO 00/74679 (Merck& Co.), asserted to be specific for melanocortin or related receptors.However, in general such compounds have at most two functionalsubstituted groups, have relatively poor affinity and specificity, andare not suitable for use as a drug compound. There is a significant needfor compounds with high specificity for discrete receptors, such asspecific melanocortin receptors, as well as compounds that are agonists,inverse agonists, or antagonists for such receptors. High affinitycompounds for such receptors can be used to exploit varied physiologicalresponses associated with the receptors, either as agonists orantagonists. There is thus a need for compounds that are more selective,including higher affinity and specificity, and in particular forcompounds that have at least four biologically active substitutedgroups. This invention addresses that need.

[0012] WO 02/085925, “Melanocortin Receptor Ligands”, to The Proctor &Gamble Company, discloses ketopiperazine structures and methods ofsynthesis thereof, but does not disclose piperazine structures,piperazine structures with four substituted groups, methods tosynthesize piperazine structures, methods to synthesize piperazine orketopiperazine structures with four substituted groups, or methods tosynthesize optically pure structures, and further does not disclosestructures with a single substituent group that is a single D-Pheresidue, or a derivative or homolog thereof, optionally with an aminecapping group.

[0013] With respect to certain objects, methods, synthetic schemes,utilities, applications, definitions, protocols and other disclosures,this application is related to PCT/US02/25574, entitled Peptidomimeticsof Biologically Active Molecules, filed on Aug. 12, 2002; toPCT/US01/50075, entitled Identification of Target-Specific Folding Sitesin Peptides and Proteins, filed on Dec. 19, 2001; and to U.S. patentapplication Ser. No. 10/762,079, entitled PiperazineMelanocortin-Specific Compounds, filed on Jan. 20, 2004; and thespecifications of each of the foregoing are incorporated herein byreference as if set forth in full.

BRIEF SUMMARY OF THE INVENTION

[0014] In one embodiment, the invention provides a compound having theformula of structure I:

[0015] or an enantiomer, stereoisomer or diastereoisomer thereof, or apharmaceutically acceptable salt thereof,

[0016] wherein

[0017] X is CH₂, C═O or C═S;

[0018] R₁ is -L₁-J;

[0019] One of R_(2a) and R_(2b) is -L₂—W and the remaining of R_(2a) andR_(2b) is hydrogen;

[0020] R₃ is -L₃-Q;

[0021] L₁ is a bond or a linker unit comprising from one to eightbackbone atoms selected from the group consisting of carbon, sulfur,oxygen or nitrogen;

[0022] J is a ring structure selected from the group consisting ofsubstituted or unsubstituted aromatic carbocyclic rings, substituted orunsubstituted non-aromatic carbocyclic rings, substituted orunsubstituted aromatic fused carbobicyclic ring groups, two substitutedor unsubstituted aromatic carbocyclic rings wherein the rings are joinedby a bond or —O—, and substituted or unsubstituted aromatic fusedheterobicyclic ring groups; wherein in each instance the rings include 5or 6 ring atoms;

[0023] L₂ is a bond or —(CH₂)_(y)—;

[0024] W is a heteroatom unit with at least one cationic center,hydrogen bond donor or hydrogen bond acceptor wherein at least oneheteroatom is nitrogen or oxygen;

[0025] L₃ is a bond or a linker unit comprising from one to ninebackbone atoms selected from the group consisting of carbon, sulfur,oxygen or nitrogen;

[0026] Q is an aromatic carbocyclic ring selected from the groupconsisting of phenyl, substituted phenyl, naphthyl and substitutednaphthyl;

[0027] One or two of R_(4a), R_(4b), R_(5a), and R_(5b) areindependently -L₂-W or a C₁ to C₆ aliphatic linear or branched chain andthe remaining of R_(4a), R_(4b), R_(5a), and R_(5b) are hydrogen,provided that at least one of R_(4a) and R_(4b) and at least one ofR_(5a) and R_(5b) are hydrogen; and

[0028] y is at each occurrence independently from 1 to 6.

[0029] In one embodiment of the invention, X is CH₂ in the compound ofstructure I.

[0030] In another embodiment of the invention, in the compound ofstructure I, L₁ may be a linker unit selected from the group consistingof:

[0031] —(CH₂)_(y)—,

[0032] —(CH₂)_(y)—O—,

[0033] —(CH₂)_(y)—C(═O)

[0034] —(CH₂)_(y)—NH—,

[0035] —(CH₂)_(y)—NH—C(═O)—,

[0036] —(CH₂)_(y)—C(═O)—NH—,

[0037] —(CH₂)_(y)C(═O)O,

[0038] —(CH₂)_(y)S

[0039] —(CH₂)_(y)—SO₂—NH—,

[0040] —NH—C(═O)—,

[0041] —NH—C(═O)-(CH₂)_(y)—,

[0042] —NH—SO₂—(CH₂)_(y)—,

[0043] —NH—(CH₂)_(y)—,

[0044] —NH—(CH₂)_(y)—O—,

[0045] —SO₂—(CH₂)_(y)—,

[0046] —C(═O)—NH—,

[0047] —C(═O)—NH—(CH₂)_(y)—,

[0048] —C(═O)-(CH₂)_(y)—,

[0049] —C(═O)— and

[0050] —C(═O)—O—(CH₂)_(y)—,

[0051] where y is from 1 to 6.

[0052] In another embodiment of the invention, in the compound ofstructure I, J is a substituted or unsubstituted ring structure selectedfrom the group consisting of

[0053] In another embodiment of the invention J is substituted with oneor more ring substituents independently selected from the groupconsisting of hydroxyl, halogen, sulfonamide, alkyl or aryl groupsattached directly or through an ether linkage in the compound ofstructure I.

[0054] In another embodiment of the invention, in the compound ofstructure I, L₂ is (CH₂)_(y) wherein y is between 1 and 4.

[0055] In another embodiment of the invention, in the compound ofstructure I, W is a heteroatom unit with at least one cationic centerselected from the group consisting of —NH₂ and —NH—C(═NH)—NH₂.

[0056] In another embodiment of the invention, in the compound ofstructure I, W may be a heteroatom unit with at least one cationiccenter, hydrogen bond donor or hydrogen bond acceptor selected from thegroup consisting of:

[0057] —NH—C(═O)—CH₃,

[0058] —C(═O)—NH—CH₃,

[0059] —NH—C(═NH)—NH—CH₃,

[0060] —NH—C(═NH)—NH—CH₂—CH₃,

[0061] —NH—C(═NH)—NH—CH₂—CH₂—CH₃,

[0062] —NH—C(═NH)—NH₂,

[0063] —NH—C(═O)—O—CH₃,

[0064] —NH—C(═O)—CH₃,

[0065] —NH—C(═O)—NH₂,

[0066] —NH—C(═O)—NH—CH₃,

[0067] —NH—SO₂—NH₂,

[0068] —NH—SO₂—CH₃,

[0069] —C(═O)—NH₂,

[0070] —OH,

[0071] In another embodiment of the invention, in the compound ofstructure I, L₃ may be a linker unit selected from the group consistingof:

[0072] —(CH₂)_(y)—,

[0073] —(CH₂)_(y)—O—,

[0074] —(CH₂)_(y)OC(═O)

[0075] —(CH₂)_(y)—N(R_(6a),R_(6b))—,

[0076] —(CH₂)_(y)NR_(6a)—C(═O)—,

[0077] —(CH₂)_(y)—CH(NR_(6a)R_(6b))-(CH₂)_(y)—,

[0078] —(CH₂)_(y)C(═O)CH(NR_(6a)R_(6b))(CH₂)_(y)—,

[0079] —(CH₂)_(y)C(═O)—,

[0080] —(CH₂)_(y)—C(═O)—NH—,

[0081] —(CH₂)_(y)—CH(CH₃)—O—,

[0082] —(CH₂)_(y)—CH(CH₃)—C(═O)—,

[0083] —(CH₂)_(y)C(═O)—,

[0084] —(CH₂)_(y)C(═O)S—,

[0085] —(CH₂)_(y)—S—,

[0086] —(CH₂)_(y)—S—S—,

[0087] —(CH₂)_(y)—SO₂—NH—,

[0088] —NH—C(═O)—,

[0089] —NH—C(═O)-(CH₂)_(y)—,

[0090] —NH—SO₂—(CH₂)_(y)—,

[0091] —NH—(CH₂)_(y)—,

[0092] —NH—(CH₂)_(y)—O—,

[0093] —NH—(CH₂)_(y)—NH—,

[0094] —NH—(CH₂)_(y)—NH—C(═O)—,

[0095] —NH—(CH₂)_(y)—C(═O)—NH—,

[0096] —NH—(CH₂)_(y)—S—,

[0097] —NH—(CH₂)_(y)—S—S,

[0098] —NH—(CH₂)_(y)—C(═O)—,

[0099] SO₂—(CH₂)_(y)—,

[0100] —C(═O)-(CH₂)_(y)C(═O)—,

[0101] —C(═O)-(CH₂)_(y)—C(═O)—NH—,

[0102] —C(═O)-(CH₂)_(y)—NH—C(═O)—,

[0103] —C(═O)—NH—,

[0104] —C(═O)—NH—(CH₂)_(y)—,

[0105] —C(═O)CH(NR_(6a),R_(6b))(CH₂)_(y)—,

[0106] —C(═O)-(CH₂)_(y)—O—,

[0107] —C(═O)—CH(CH₃)—O—,

[0108] —C(═O)—CH(CH₃)—NH—,

[0109] —C(═O)—CH(CH₃)—NH—C(═O)—,

[0110] —C(═O)-(CH₂)_(y)—,

[0111] —C(═O)-(CH₂)_(y)CH(NR_(6a),R_(6b))—,

[0112] —C(═O)-(CH₂)_(y)—CH(NR₆,R_(6b))-(CH₂)_(y)—,

[0113] —C(═O)-(CH₂)_(y)CH(NHR_(6a),R_(6b))—C(═O)—,

[0114] —C(═O)-(CH₂)_(y)S,

[0115] —C(═O)-(CH₂)_(y)—S—S—,

[0116] —C(═O)—,

[0117] —C(═O)—O—(CH₂)_(y)—,

[0118] wherein

[0119] R_(6a) and R_(6b) are each independently selected from the groupconsisting of hydrogen, R₇ and R₇—R₈;

[0120] R₇ is an amino acid residue or an amine capping group, providedthat if R₈ is present, R₇ is an amino acid residue;

[0121] R₈ is H or an amine capping group; and

[0122] y is from 1 to 6, provided that where any linker unit includestwo y index values, the total of such y index values is from 2 to 6.

[0123] In the compound of structure I, the amino acid residue at R₇, ifprovided, may be an L-amino acid selected from the group consisting ofAbu, 2-Abz, 3-Abz, 4-Abz, Achc, Acpc, Aib, Amb, Arg(Tos), Asp(anilino),Asp(3-Cl-anilino), Asp(3,5-diCl-anilino), 11-Aun, AVA, Beta-hHyp(Bzl),Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA, GBzA, B-Gpa, GVA(Cl), His,hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp, 2-Naphthylacetyl, (Nlys)Gly,OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr, Sar, Tle, Tiq, Atc, IgI,Hyp(2-Naphthyl), Hyp(Phenyl), 2-Aic, Idc, 1-Aic, Beta-homoSer(Bzl),Ser(2-Naphthyl), Ser(Phenyl), Ser(4-Cl-Phenyl), Ser(2-Cl-Phenyl),Thr(Bzl), Tic, Beta-homoThr(Bzl), Thr(2-Naphthyl), Thr(Phenyl),Thr(4-Cl-Phenyl) and Thr(2-Cl-Phenyl), Nle, Leu, Ile, Val and Beta-Ala.

[0124] In the compound of structure I, the amine capping group, ifprovided, may be selected from the group consisting of methyl, dimethyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, allyl,cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl,phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl,benzyl, benzoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx, Amc and 8-Aoc.Alternatively, the amine capping group is polyethylene glycol with aformula molecular weight of between 100 and 10,000.

[0125] In any of the foregoing descriptions of the compound of structureI, Q can be

[0126] wherein R_(9a) and R_(9b) are optional ring substituents, andwhen one or both are present, are the same or different andindependently hydroxyl, halogen, alkyl, or aryl groups attached directlyor through an ether linkage. In one embodiment, at least one of R_(9a)or R_(9b) is an alkyl selected from the group consisting of —CH₃ and—OCH₃. In another embodiment, at least one of R_(9a) or R_(9b) is ahalogen selected from the group consisting of —Cl and —CF₃.

[0127] In another embodiment of the invention, in the compound ofstructure I, one of R_(4a), R_(4b), R_(5a), and R_(5b) is a C₁ to C₆aliphatic linear or branched chain. In another preferred embodiment, oneof R_(4a) or R_(4b) and one of R_(5a) and R_(5b) is a C₁ to C₆ aliphaticlinear or branched chain. In either instance, the C₁ to C₆ aliphaticlinear or branched chain can be selected from the group consisting ofmethyl and isobutyl.

[0128] In another embodiment of the invention, in the compound ofstructure I the following assignments obtain:

[0129] X is CH₂;

[0130] L₁ is a linker unit selected from the group consisting of—(CH₂)₃—, —(CH₂)₂—, —CH₂—, —C(═O)—CH₂—, —C(═O)-(CH₂)₂— and—C(═O)-(CH₂)₃—;

[0131] J a ring structure selected from the group consisting ofnaphthyl, phenyl, substituted phenyl, indole and substituted indole;

[0132] L₂ is (CH₂)₃;

[0133] W is —NH—C(═NH)—NH₂;

[0134] L₃ is a linker unit selected from the group consisting of—C(═O)-(C—NR_(6a)R_(6b))-(CH₂)_(y)—, —C(═O)-(CH₂)_(y)— and—(CH₂)_(y)—(C—NR_(6a)R_(6b))-(CH₂)_(y)—;

[0135] Q is an aromatic carbocyclic ring selected from the groupconsisting of phenyl, substituted phenyl and naphthyl;

[0136] One of R_(4a), R_(4b), R_(5a), and R_(5b) is methyl or isobutyl,and the remaining of R_(4a), R_(4b), R_(5a), and R_(5b) are hydrogen;

[0137] R_(6a) and R_(6b) are each independently selected from the groupconsisting of hydrogen and R₇; and

[0138] R₇ is selected from the group consisting of acetyl, methyl,dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, benzoyl,hexanoyl, and polyethylene glycol.

[0139] Thus in one embodiment the invention includes the followingcompounds and pharmaceutically acceptable salts thereof:

[0140]N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0141]N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0142]N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0143]N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-6(S)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0144]N-{3-[1-[2(R)-Amino-3-(2-chloro-4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0145]N-{3-[1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0146]N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0147]N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0148]N-{3-[1-[2(R)-Amino-3-(4-chloro-2-fluoro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0149] N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0150]N-{3-[1-[2(R)-Amino-3-(2-chloro-4-trifluoromethyl-phenyl)-propionyl]-5(R)-methyl-4(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0151]N-{3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0152]N-{3-[1-[2(R)-Amino-3-(3,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0153]N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-methyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0154]N-{3-[1-[4-(4-Chloro-phenyl)-pyrrolidine-3-carbonyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0155] N-{1(R)-(4-chloro-2-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide;

[0156]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl)-guanidine;

[0157]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(3-phenyl-propyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0158]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-p-tolyl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0159]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-acetyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;

[0160]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-propionyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;

[0161]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-butyryl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;

[0162]N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-[2-(1H-indol-3-yl)-ethyl]-5(R)-methyl-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-[2-(2-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;

[0163]N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-[2-(1-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;

[0164]N-(3-{1-(2(R)-Amino-(4-chloro-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;

[0165]N-(3-{1-(2(R)-Amino-(4-chloro-2-methyl-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;

[0166]N-{3-[1-[2(R)-Amino-3-(phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0167]N-{3-[1-[2(R)-Amino-3-(4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0168]N-{3-[1-[2(R)-Amino-3-(4-methoxy-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-dimethylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(b)-yl]-propyl}-guanidine;

[0169]N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-methylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0170]N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-diethylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0171]N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-isopropylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0172]N-{3-[1-[2(R)-Amino-3-naphthalen-2-yl-propionyl]-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0173]N-{2-[2(S)-(3-Guanidino-propyl)-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;

[0174]N-{1(R)-(2,4-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide;

[0175]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0176]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(3H-imidazol-4-ylmethyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;

[0177]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(4-imidazol-1-yl-benzyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;

[0178]N-{2-[2(S)-(3-Guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;

[0179]N-{2-[4-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-methanesulfonamide;

[0180]N-{2-[4-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;

[0181]N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)_(j)-piperazin-Z(S)-yl]-propyl}-guanidine;

[0182]N-{3-[1-[2(R)-Amino-3-(4-chloro-2-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0183]N-{1(R)-(2,4-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide;

[0184] 2(S)-Amino-N-{1(R)-(2,4-dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acethyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamide

[0185]N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-3(S)-yl]-propyl}-guanidine

[0186]N-[2-[4-[2(R)-Acetylamino-3-(4-chloro-phenyl)-propionyl]-2(S),5(S)-bis-(3-guanidino-propyl)-piperazin-1-yl]-1(R)-(4-chloro-benzyl)-2-oxo-ethyl]-acetamide;

[0187]N-{3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine;

[0188]N-(3-{1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-3-oxo-4-phenethyl-piperazin-2(S)-yl}-propyl)-guanidine;

[0189]N-(3-{1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-4-[2-(1H-indol-3-yl)-ethyl]-5(R)-methyl-3-oxo-piperazin-2(S)-yl}-propyl)-guanidine;

[0190]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine;

[0191] 2(S)-Amino-N-{1(R)-(4-chloro-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamide;

[0192] 2(S)-Amino-N-{1(R)-(2,4-dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamide;

[0193]N-{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine;

[0194]N-{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-piperazin-2(S)-yl]-propyl}-guanidine;

[0195]N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R),6(R)-dimethyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;

[0196]N-{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-piperazin-2(S)-yl]-propyl}-guanidine;

[0197]N-{2-[4-(2(R)-Amino-3-(2,4-dimethyl-phenyl)-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-benzyl-2-oxo-ethyl}-acetamide;

[0198]N-{2-[4-(2(R)-Amino-3-(2,4-dimethyl-phenyl)-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-(3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-2-oxo-ethyl]-acetamide;

[0199] N-{1(R)-Benzyl-2-[4-[3-(2,4-dichloro-phenyl)-propionyl]-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-2-oxo-ethyl}-acetamide;

[0200]N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine;

[0201]N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl}-propyl)-guanidine;

[0202]N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(4-phenyl-butyryl)-piperazin-2(S)-yl}-propyl)-guanidine;

[0203]N-(3-{1-[3-(2,4-Dichloro-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine;

[0204]N-{3-[1-(2(R)-Amino-2-phenyl-acetyl)-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl]-propyl}-guanidine;and

[0205]N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-isobutyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0206] In yet another embodiment, the invention can be characterized asa compound of the formula of structure II:

[0207] wherein

[0208] R₁₀ is H or ═O;

[0209] Z is N, NH, CH, CH₂ or N—CH₃;

[0210] R₁₁, R₁₂, R₁₃ and R₁₄ are independently hydrogen or a C₁ to C₆linear or branched chain on the proviso that either R₁₁, and R₁₂, or, ifn is 1, R₁₂ and R₁₃, can constitute an aromatic or non-aromaticcarbocyclic ring;

[0211] R₁₅, R₁₆, and R₁₉ are independently hydrogen or a hydroxyl,halogen, alkyl or aryl groups attached directly or through an etherlinkage;

[0212] R₁₇ and R₁₈ are independently hydrogen, a hydroxyl, halogen,alkyl or aryl groups attached directly or through an ether linkage, ortogether constitute a fused aromatic ring;

[0213] R₂₀ is hydrogen or a C₁ to C₆ aliphatic linear or branched chain,optionally containing at least one N;

[0214] R₂₁ is optionally not present, or if present is a C₁ to C₆aliphatic linear or branched chain;

[0215] R_(22a) and R_(22b) are independently hydrogen or a C₁ to C₆linear or branched chain on the proviso that R₂₀ and one of R_(22a) andR_(22b) can form a nonaromatic heterocyclic ring;

[0216] m is from 0 to 6;

[0217] n is 0 or 1; and

[0218] the dashed lines are an optional double bond.

[0219] Compounds of the invention thus include compounds wherein one ofR_(5a) and R_(5b) is an (R)-configuration C₁ to C₆ aliphatic linear orbranched chain, preferably (R)-methyl or (R)-isobutyl, and the remainingof R_(4a), R_(4b), R_(5a), and R_(5b) are hydrogen, and optionallyfurther wherein L₁ is —CH₂—, —(CH₂)₂— or —(CH₂)₃—. In one embodiment ofthe invention, such compounds can be characterized in that they bind tothe melanocortin 4 receptor with high affinity and exhibit no intrinsicactivity at the melanocortin 4 receptor. The invention further includesa pharmaceutical composition including such compounds or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier. The invention still further includes a method oftreating obesity or feeding-related disorders, comprising administrationof a therapeutically effective amount of such a pharmaceuticalcomposition.

[0220] Compounds of the invention further include compounds wherein oneof R_(5a) and R_(5b) is an (R)-configuration C₁, to C₆ aliphatic linearor branched chain, preferably (R)-methyl or (R)-isobutyl, and theremaining of R_(4a), R_(4b), R_(5a), and R_(5b) are hydrogen and whereinL₁ is selected from the group consisting of —C(═O)—CH₂—, —C(═O)-(CH₂)₂—and —C(═O)-(CH₂)₃—. In one embodiment of the invention, such compoundscan be characterized in that they are an agonist or partial agonist atthe melanocortin 4 receptor.

[0221] In one embodiment of the invention there is provided a method oftreating obesity or feeding-related disorders, the method includingadministration of a therapeutically effective amount of a compound ofthe invention wherein the compound binds to the melanocortin 4 receptorwith high affinity and exhibits no intrinsic activity at themelanocortin 4 receptor.

[0222] In another embodiment the present invention provides a compoundthat is an agonist of a melanocortin receptor, including MC1-R, MC3-R,MC4-R, or MC5-R.

[0223] In another embodiment, the present invention provides a compoundthat is an antagonist of a melanocortin receptor, including MC1-R,MC3-R, MC4-R, or MC5-R.

[0224] In another embodiment, the present invention provides a compoundthat is an inverse agonist of a melanocortin receptor, including MC1—R,MC3-R, MC4-R, or MC5-R.

[0225] In another embodiment, the present invention provides a compoundthat is an antagonist of an inverse agonist, such as agouti-relatedprotein (AgRP), of a melanocortin receptor, including MC4-R.

[0226] In yet another embodiment, the present invention provides acompound that binds with high affinity to a melanocortin receptor,including MC1—R, MC3-R, MC4-R, or MC5-R, but which is functionallyinactive at physiologically relevant concentrations, is a weak agonistor antagonist (EC₅₀ of 100 nM or higher), is an inverse agonist or is anantagonist of an inverse agonist.

[0227] In yet another embodiment, the present invention provides acompound that binds with high affinity and specificity to MC4-R butwhich has no intrinsic activity at MC4-R, and which may be employed forattenuating food intake and body weight gain, including but not limitedto treatment of a disorder or condition such as obesity and associatedimpairment of energy homeostasis.

[0228] The invention further includes a method for altering a disorderor condition associated with the activity of a melanocortin receptor,comprising administering to a patient a therapeutically effective amounta compound of this invention. In one embodiment the disorder orcondition is an eating disorder such as cachexia. In another embodimentthe disorder or condition is obesity and associated impairment of energyhomeostasis.

[0229] A primary object of the present invention is to provideconformationally constrained isomers of tetra- or penta-substitutedpiperazines or derivatives thereof, wherein the pendant groupsubstituents are amino acid moieties, amino acid side chain moieties orderivatives thereof, such that the resulting ring compound biologicallymimics a relevant reverse turn peptide structure that is characteristicof melanocortin peptides.

[0230] Another object of the present invention is to provide tetra- orpenta-substituted piperazine compounds and derivatives thereof.

[0231] Another object of the present invention is to provide piperazinecompounds and derivatives of piperazine compounds with at least fourpendant groups, such pendant groups consisting of any moiety other thanH, O, S, or a halogen.

[0232] Another object of the present invention is to provide piperazinecore compounds wherein pendant groups are provided, which pendant groupsare or include amino acid side chain moieties.

[0233] Another object of the present invention is to provide tetra- orpenta-substituted piperazine compounds or derivatives thereof whereinsuch compounds are specific for one or more melanocortin receptors.

[0234] Another object of the present invention is to provide a methodfor synthesis of tetra-substituted piperazine compounds.

[0235] Other objects, advantages and novel features, and further scopeof applicability of the present invention will be set forth in part inthe detailed description to follow, taken in conjunction with theaccompanying drawings, and in part will become apparent to those skilledin the art upon examination of the following, or may be learned bypractice of the invention. The objects and advantages of the inventionmay be realized and attained by means of the instrumentalities andcombinations particularly pointed out in the appended claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0236] The accompanying drawings, which are incorporated into and form apart of the specification, illustrate one or more embodiments of thepresent invention and, together with the description, serve to explainthe principles of the invention. The drawings are only for the purposeof illustrating one or more preferred embodiments of the invention andare not to be construed as limiting the invention. In the drawings:

[0237]FIGS. 1A and 1B illustrate steric interaction by placement of theR₅ group in an (S)— or (R)-configuration, respectively;

[0238]FIG. 2 is a chart showing behavior in an animal model followingadministration of the compound of Example 10 or a control;

[0239]FIG. 3 is a chart of one hour food intake in an animal modelfollowing administration of the compound of Example 10 or a control;

[0240]FIG. 4 is a chart showing behavior in an animal model followingadministration of the compound of Example 6 or a control;

[0241]FIG. 5 is a chart of one hour food intake in an animal modelfollowing administration of the compound of Example 6 or a control;

[0242]FIG. 6 is a chart of saccharin intake in a conditioned tasteaversion response test of the compound of Example 10 compared topositive and negative controls;

[0243]FIG. 7 is a chart of saccharin intake in a conditioned tasteaversion response test of the compound of Example 6 compared to positiveand negative controls; and

[0244]FIG. 8 is a graph of percent change in body weight in an animalmodel of animals in growth phase for a 21 day period where negativecontrol and the compounds of Examples 6 and 10 were administered for 7days.

DETAILED DESCRIPTION OF THE INVENTION

[0245] In this invention it is disclosed that piperazine rings,including piperazine ring derivatives, may be employed with at leastfour descriptors, wherein each descriptor is a separate pendant groupunique to a given ring atom. By employing four or five descriptors, theinventors have further found that the chirality of the ring, and stereostructure generally, is fixed in a desired structure, thereby moreclosely mimicking the desired pharmacophores, and with the descriptorspositioned in the most relevant chemical space.

[0246] This invention thus discloses the use of tetra- orpenta-substituted piperazine and related derivative templates for drugdesign. The invention further also relates to enantiomerically puretetra-substituted piperazines, preferably made by the synthetic schemesdisclosed herein or variants thereof. A classic piperazine ring is aconformationally dynamic six-membered ring structure. It can exist in avariety of conformational states, commonly referred to as chair, boat,twisted chair or twisted boat conformations. Because of this dynamism instructural states, the location of descriptors on the ring plays animportant role in stabilizing the ring in a single conformational state;if the appropriate conformational state is selected, this is conduciveto making a molecule more selective for its receptor in terms of bindingaffinity and intrinsic functional activity. For example, a 1,3 axialplacement of two bulky descriptors generally causes unfavorable stericinteractions between these two groups, and thus make a chairconformation energetically less stable. Consequently, the chairconformation is less preferred, resulting in a twisted chair or boatconformation. The twisted chair or boat conformation results in aspecific stereochemical alignment of the descriptors, which isspecifically relevant to interaction with the desired receptor. Thus aconformation resulting from 1,3 axial placement of two descriptors mayresult in a structure more selective for a given receptor sub-type.

[0247] In one broad aspect, the invention describes and discloses theuse of tetra- or penta-substituted piperazine and relatedpiperazine-derivative ring compounds as biologically active agents. In arelated aspect, the invention describes and discloses the use of tetra-or penta-substituted piperazine and related piperazine-derivative ringcompounds as mimetics of desired pharmacophores, including but notlimited to pharmacophores derived from biologically activemetallopeptides, which biologically active metallopeptides may in turnbe derived from biologically active peptides, polypeptides or proteins.

[0248] In yet another embodiment, the invention describes tetra- orpenta-substituted piperazine and related piperazine-derivative ringcompounds specific for G-protein coupled receptor systems, such systemsincluding, but not limited to, melanotropin or melanocortin receptors(MC1-R, MC3-R, MC4-R and MC5-R).

[0249] In yet another embodiment, the invention provides novel schemesand methods of synthesis of tetra-substituted piperazine and relatedpiperazine-derivative ring compounds.

[0250] Definitions. Before proceeding further with the description ofthe invention, certain terms are defined as set forth herein.

[0251] The “amino acid” and “amino acids” used in this invention, andthe terms as used in the specification and claims, include the knownnaturally occurring protein amino acids, which are referred to by boththeir common three letter abbreviation and single letter abbreviation.See generally Synthetic Peptides: A User's Guide, GA Grant, editor, W.H. Freeman & Co., New York, 1992, the teachings of which areincorporated herein by reference, including the text and table set forthat pages 11 through 24. As set forth above, the term “amino acid” alsoincludes stereoisomers and modifications of naturally occurring proteinamino acids, non-protein amino acids, post-translationally modifiedamino acids, enzymatically synthesized amino acids, derivatized aminoacids, constructs or structures designed to mimic amino acids, and thelike. Modified and unusual amino acids are described generally inSynthetic Peptides: A User's Guide, cited above; Hruby V J, Al-obeidi Fand Kazmierski W: Biochem J 268:249-262, 1990; and Toniolo C: Int JPeptide Protein Res 35:287-300, 1990; the teachings of all of which areincorporated herein by reference.

[0252] The term “amino acid side chain moiety” used in this inventionincludes any side chain of any amino acid, as the term “amino acid” isdefined herein, including any derivative of an amino acid side chainmoiety, as the term “derivative” is defined herein. Therefore, thisincludes the side chain moiety present in naturally occurring aminoacids. It further includes side chain moieties in modified naturallyoccurring amino acids, such as glycosylated amino acids. It furtherincludes side chain moieties in stereoisomers and modifications ofnaturally occurring protein amino acids, non-protein amino acids,post-translationally modified amino acids, enzymatically synthesizedamino acids, derivatized amino acids, constructs or structures designedto mimic amino acids, and the like. For example, the side chain moietyof any amino acid disclosed herein is included within the definition ofan amino acid side chain moiety.

[0253] The “derivative” of an amino acid side chain moiety includes anymodification to or variation in any amino acid side chain moieties,including a modification of naturally occurring amino acid side chainmoieties. By way of example, derivatives of amino acid side chainmoieties include straight chain or branched, cyclic or noncyclic,substituted or unsubstituted, and saturated or unsaturated alkyl, arylor aralkyl moieties.

[0254] The following abbreviations for amino acids, amino acid sidechain moieties and derivatives and constituents thereof have themeanings giving, it being understood that any amino acid may be ineither the L- or D-configuration: Abu gamma-amino butyric acid 2-Abz2-amino benzoic acid 3-Abz 3-amino benzoic acid 4-Abz 4-amino benzoicacid Achc 1-amino-cyclohexane-1-carboxylic acid Acpc1-amino-cyclopropane-1-carboxylic acid 12-Ado 12-amino dodecanoic acidAib alpha-aminoisobutyric acid 1-Aic 2-aminoindane-1-carboxylic acid2-Aic 2-aminoindane-2-carboxylic acid 6-Ahx 6-amino hexanoic acidBeta-Ala Bate-alanine Amb 4-(aminomethyl)-benzoic acid Amc4-(aminomethyl)-cyclohexane carboxylic acid 7′-amino-heptanoylNH₂—(CH₂)₆CO— 8-Aoc 8-amino octanoic acid Arg(Tos)N^(G)-para-tosyl-arginine Asp(anilino) beta-anilino-aspartic acidAsp(3-Cl-anilino) beta-(3-chloro-anilino)-aspartic acidAsp(3,5-diCl-anilino) beta-(3,5-dichloro anilino)-aspartic acid Atc2-aminotetralin-2-carboxylic acid 11-Aun 11-amino undecanoic acid AVA5-amino valeric acid Beta-hHyp(Bzl) Beta-(O-benzyl)-homohydroxyprolineBeta-hSer(Bzl) Beta-(O-benzyl)-homoserine Bip biphenylalanine Bzl benzylBz benzoyl Cha cyclohexylalanine Chg cyclohexylglycine Cmpi4-caboxymethyl-piperazine Cys(Bzl) S-benzyl-cysteine Dip3,3-diphenylalanine Disc 1,3-dihydro-2H-isoindolecarboxylic acidDpr(beta-Ala) N^(beta)-(3-aminopropionyl)-alpha,beta- diaminopropionicacid Et ethyl GAA epsilon-guanidino acetic acid GBzA 4-guanidino benzoicacid B-Gpa 3-guanidino propionic acid GVA(Cl)beta-chloro-epsilon-guanidino valeric acid Heptanoyl CH₃—(CH₂)₅CO— hPhehomophenylalanine hSer homoserine Hyp hydroxy proline hHyp homo hydroxyproline Hyp(Bzl) O-benzyl-hydroxyproline Hyp(2-naphthly) O-2′naphthyl-hydroxyproline Hyp(Phenyl) O-phenyl-hydroxyproline Idcindoline-2-carboxylic acid Igl indanylglycine Inp isonipecotic acidLys(Z) N-epsilon-benzyloxycarbonyl-lysine Me methyl Nal 13-(1-naphthyl)alanine Nal 2 3-(2-naphthyl)alanine (N-Bzl)Nal 2N-benzyl-3-(2-naphthyl) alanine 2-Naphthylacetyl 2-naphthyl-CH₂CO—(Nlys)Gly N-(4-aminobutyl)-glycine (N-PhEt)Nal 2N(2-phenylethyl)-3-(2-naphthyl) alanine OcHx cyclohexyl ester Phgphenylglycine Phe(4-F) para-fluoro-phenylalanine Phe(4-Br)4-bromo-phenylalanine Phe(4-CF₃) 4-trifluoromethyl-phenylalaninePhe(4-Cl) 4-chloro-phenylalanine Phe(3-Cl) 3-chloro-phenylalaninePhe(2-Cl) 2-chloro-phenylalanine Phe(2,4-diCl)2,4,-dichloro-phenylalanine Phe(2,4-diF) 2,4-difluoro-phenylalaninePhe(3,4-diCl) 3,4,-dichloro-phenylalanine Phe(5-Cl)5-chloro-phenylalanine Phe(2-Cl,4-Me) 2-chloro-4-methyl-phenylalaninePhe(2-Me,4-Cl) 4-chloro-2-methyl-phenylalanine Phe(2-F,4-Cl)4-chloro-2-fluoro-phenylalanine Phe(2,4-diMe) 2,4-dimethyl-phenylalaninePhe(2-Cl,4-CF₃) 2-chloro-4-trifluoromethyl-phenylalanine Phe(3,4-diF)3,4,-difluoro-phenylalanine Phe(4-l) 4-iodo-phenylalaninePhe(3,4-di-OMe) 3,4,-dimethoxy-phenylalanine Phe(4-Me)4-methyl-phenylalanine Phe(4-OMe) 4-methoxy-phenylalanine Phe(4-NC)4-cyano-phenylalanine Phe(4-NO₂) 4-nitro-phenylalanine Pip pipecolicacid Pr propyl Pr-i isopropyl 4-phenylPro4-phenyl-pyrrolidin-2-carboxylic acid 5-phenylPro5-phenyl-pyrrolidin-2-carboxylic acid 3-Pya 3-pyridylalanine Pyrpyroglutamic acid Qal(2′) beta-(2-quinolyl)-alanine Sal 3-styrylalanineSar sarcosine Ser(Bzl) O-benzyl-serine Ser(2-Naphthyl)O-2-Naphthyl-serine Ser(Phenyl) O-2-Phenyl-serine Ser(4-Cl-Phenyl)O-4-Cl-Phenyl-serine Ser(2-Cl-Phenyl) O-2-Cl-Phenyl-serine Ser(p-Cl-Bzl)O-4-Cl-Benzyl-serine Thr(Bzl) O-Benzyl-threonine Thr(2-Naphthyl)O-(2-naphthyl)-threonine Thr(Phenyl) O-phenyl-threonine Thr(4-Cl-Phenyl)O-(4-Cl-phenyl)-threonine Thr(2-Cl-Phenyl) O-(2-Cl-phenyl)-threonineBeta-homoThr(Bzl) O-Benzyl-bate-homothreonine Tic1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Tiq1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Tle tert-butylalanineTpi 1,2,3,4-tetrahydronorharman-3-carboxylic acid Tyr(Bzl)O-benzyl-tyrosine Tyr(2,6-DiCl-Bzl) O-(2,6 dichloro)benzyl-tyrosine

[0255] Conventional amino acid residues have their conventional meaningas given in Chapter 2400 of the Manual of Patent Examining Procedure,7^(th) Ed. Thus, “Nle” is norleucine, “Asp” is aspartic acid, “His” ishistidine, “D-Phe” is D-phenylalanine, “Arg” is arginine, “Trp” istryptophan, “Lys” is lysine, “Gly” is glycine, “Pro” is praline, “Tyr”is tyrosine, “Ser” is serine and so on.

[0256] The following amino acids, or side chains thereof, may beemployed, in either the L- or D-configuration as appropriate, in certainembodiments of this invention:

[0257] The term “homolog” includes, without limitation, (a) a D-aminoacid residue or side chain substituted for an L-amino acid residue sidechain, (b) a post-transiationally modified residue or side chainsubstituted for the residue or side chain, (c) a non-protein or othermodified amino acid residue or side chain based on another such residueor side chain, such as phenylglycine, homophenylalanine,ring-substituted halogenated, and alkylated or arylated phenylalaninesfor a phenylalanine residue, diamino proionic acid, diamino butyricacid, ornithine, lysine and homoarginine for an arginine residue, andthe like, and (d) any amino acid residue or side chain, coded orotherwise, or a construct or structure that mimics an amino acid residueor side chain, and which has at least a similarly charged side chain(neutral, positive or negative), preferably a similar hydrophobicity orhydrophilicity, and preferably a similar side chain in terms of being asaturated aliphatic side chain, a functionalized aliphatic side chain,an aromatic side chain or a heteroaromatic side chain.

[0258] The term “alkene” includes unsaturated hydrocarbons that containone or more double carbon-carbon bonds. Examples of such alkene groupsinclude ethylene, propene, and the like.

[0259] The term “alkenyl” includes a linear monovalent hydrocarbonradical of two to six carbon atoms or a branched monovalent hydrocarbonradical of three to six carbon atoms containing at least one doublebond; examples thereof include ethenyl, 2-propenyl, and the like.

[0260] The “alkyl” groups specified herein include those alkyl radicalsof the designated length in either a straight or branched configuration.Examples of such alkyl radicals include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl,isohexyl, and the like.

[0261] The term “alkynal” includes a linear monovalent hydrocarbonradical of two to six carbon atoms or a branched monovalent hydrocarbonradical of three to six carbon atoms containing at least one triplebond; examples thereof include ethynyl, propynal, butynyl, and the like.

[0262] The term “aryl” includes a monovalent or bicyclic aromatichydrocarbon radical of 6 to 12 ring atoms, and optionally substitutedindependently with one or more substituents selected from alkyl,haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano,amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, oralkoxy-carbonyl. Examples of an aryl group include phenyl, biphenyl,naphthyl, 1-naphthyl, and 2-naphthyl, derivatives thereof, and the like.

[0263] The term “aralkyl” includes a radical—R^(a)R^(b) where R^(a) isan alkylene (a bivalent alkyl) group and R^(b) is an aryl group asdefined above. Examples of aralkyl groups include benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like.

[0264] The term “aliphatic” includes compounds with hydrocarbon chains,such as for example alkanes, alkenes, alkynes, and derivatives thereof.

[0265] The term “acyl” includes a group RCO—, where R is an organicgroup. An example is the acetyl group CH₃CO—.

[0266] A group or aliphatic moiety is “acylated” when an alkyl orsubstituted alkyl group as defined above is bonded through one or morecarbonyl [—(C═O)-] groups.

[0267] An “omega amino derivative” includes an aliphatic moiety with aterminal amino group. Examples of omega amino derivatives includeaminoheptanoyl and the amino acid side chain moieties of ornithine andlysine.

[0268] The term “heteroaryl” includes mono- and bicyclic aromatic ringscontaining from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur. 5- or 6-membered heteroaryl are monocyclic heteroaromatic rings;examples thereof include thiazole, oxazole, thiophene, furan, pyrrole,imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole,oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.Bicyclic heteroaromatic rings include, but are not limited to,benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole,benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole,isoquinoline, purine, furopyridine and thienopyridine.

[0269] An “amide” includes compounds that have a trivalent nitrogenattached to a carbonyl group (—CO.NH₂), such as methylamide, ethylamide,propylamide, and the like.

[0270] An “imide” includes compounds containing an imido group(—CO.NH.CO—).

[0271] An “amine” includes compounds that contain an amino group (—NH₂).

[0272] A “nitrile” includes compounds that are carboxylic acidderivatives and contain a (—CN) group bound to an organic group.

[0273] An amino acid side chain moiety is “hydrogen bonding” when theside chain includes hydrogen donors or alternatively hydrogen acceptors.

[0274] An “amine capping group” includes any terminal group attachedthrough a terminal amine, including but not limited to any omega aminoderivative, acyl group or terminal aryl or aralkyl including groups suchas methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl,propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl,cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx,Amc or 8-Aoc, as well as terminal groups such polyethylene glycol (PEG)with an average or formula molecular weight of between 100 and 10,000,optionally a PEG carboxylic acid derivative capable of forming acovalent bond with a terminal amine.

[0275] The term “composition”, as in pharmaceutical composition, isintended to encompass a product comprising the active ingredient(s), andthe inert ingredient(s) that make up the carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and oneor more pharmaceutically acceptable carriers, and optionally one or morepharmaceutically active ingredients and agents.

[0276] A variety of chemicals and compounds are employed in thisinvention, and the following abbreviations have the meanings given: AcOHacetic acid Boc tertiary butyloxycarbonyl Cbz benzyloxycarbonyl DCMdichloromethane DEAD diethyl azodicarboxylate DIAD diisopropylazodicarboxylate DIC 1,3-diisopropylcarbodiimide DMFN,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate Fmoc9-fluorenylmethoxycarbonyl HBTU2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyiuronium hexafluorophosphateHEPES 4-(2-hydroxyethyl)1-piperazineethanesulfonic acid HOAt1-hydroxy-7-azabenzotriazole IBCF isobutyl chloroformate LAH lithiumaluminum hydride NMM N-methyl-morpholine NMP 1-methyl-2-pyrrolidinonePrt A protecting group, such as Boc, Cbz or Fmoc TBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborateTEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TPPtriphenylphosphine

[0277] A “tetra-substituted piperazine” or “penta-substitutedpiperazine”, as used herein, is a piperazine compound or derivativethereof wherein a group other than solely H, and preferably including anamino acid residue or an amino acid side chain moiety, is attached toeach ring N member, and further wherein a group other than solely H, O,S or a halogen, preferably including an amino acid side chain moiety, isattached to two ring C members for a tetra-substituted piperazine and tothree ring C members for a penta-substituted piperazine.

[0278] “Sexual dysfunction” means any condition that inhibits or impairsnormal sexual function, including coitus. The term is not limited tophysiological conditions, and includes psychogenic conditions orperceived impairment without a formal diagnosis of pathology ordisorder. Sexual dysfunction includes erectile dysfunction in a malemammal and female sexual dysfunction in a female mammal.

[0279] “Erectile dysfunction” is a disorder involving the failure of amale mammal to achieve functional erection, ejaculation, or both.Erectile dysfunction is accordingly synonymous with impotence, andincludes the inability to attain or sustain an erection of sufficientrigidity for coitus. Symptoms of erectile dysfunction includes aninability to achieve or maintain an erection, ejaculatory failure,premature ejaculation, or inability to achieve an orgasm. An increase inerectile dysfunction is often associated with age or may be caused by aphysical disease or as a side-effect of drug treatment.

[0280] “Female sexual dysfunction” is a disorder including sexualarousal disorder. The term “sexual arousal disorder” includes apersistent or recurrent failure to attain or maintain thelubrication-swelling response of sexual excitement until completion ofsexual activity. Sexual dysfunction in females can also includeinhibited orgasm and dyspareunia, which is painful or difficult coitus.Female sexual dysfunction includes, but is not limited to, a number ofcategories of diseases, conditions and disorders including hypoactivesexual desire disorder, sexual anhedonia, sexual arousal disorder,dyspareunia and vaginismus. Hypoactive sexual desire disorder includes adisorder in which sexual fantasies and desire for sexual activity arepersistently or recurrently diminished or absent, causing markeddistress or interpersonal difficulties. Hypoactive sexual desiredisorder can be related to boredom or unhappiness in a long-standingrelationship, depression, dependence on alcohol or psychoactive drugs,side effects from prescription drugs, or hormonal deficiencies. Sexualanhedonia includes decreased or absent pleasure in sexual activity.Sexual anhedonia can be caused by depression, drugs, or interpersonalfactors. Sexual arousal disorder can be caused by reduced estrogen,illness, or treatment with diuretics, antihistamines, antidepressants,or antihypertensive agents. Dyspareunia and vaginismus are sexual paindisorders characterized by pain resulting from penetration and may becaused, for example, by medications which reduce lubrication,endometriosis, pelvic inflammatory disease, inflammatory bowel diseaseor urinary tract problems.

[0281] By a melanocortin receptor “agonist” is meant an endogenous ordrug substance or compound, including a compound of this invention thatcan interact with a melanocortin receptor and initiate a pharmacologicalresponse, including but not limited to adenyl cyclase expression,characteristic of the melanocortin receptor. By a melanocortin receptor“antagonist” is meant a drug or a compound, including a compound of thisinvention, that opposes the melanocortin receptor-associated responsesnormally induced by a melanocortin receptor agonist agent, but withoutitself initiating a pharmacological response characteristic of themelanocortin receptor, such as increasing or decreasing adenyl cyclaseexpression. By a melanocortin receptor “inverse agonist” is meant a drugor a compound, including a compound of this invention, that is anantagonist with respect to an agonist, and which by itself induces orinitiates a pharmacological response characteristic of the melanocortinreceptor, such as reducing basal or constitutive adenyl cyclaseexpression.

[0282] By “binding affinity” is meant the ability of a compound or drugto bind to its biological target.

[0283] By “intrinsic activity” is meant the maximal stimulation ofadenyl cyclase achievable by a compound in a melanocortin receptor cellsystem. The maximal stimulation achieved by A-MSH or NDP-α-MSH isdesignated as an intrinsic activity of 1.0 (or 100%) and a compoundcapable of stimulating half the maximal activity that of α-MSH orNDP-α-MSH is designated as having an intrinsic activity of 0.5 (or 50%).A compound of this invention that under assay conditions describedherein has an intrinsic activity of 0.7 (70%) or higher is classified asan agonist, a compound with intrinsic activity between 0.1 (10%) and 0.7(70%) is classified as a partial agonist, and a compound with intrinsicactivity below 0.1 (10%) is classified as inactive or having nointrinsic activity. Compounds with intrinsic activity below 0.1 (10%)were further evaluated, as indicated herein, for antagonist effect.

[0284] Clinical Applications. The compounds disclosed herein can be usedfor both medical applications and animal husbandry or veterinaryapplications. Typically, the product is used in humans, but may also beused in other mammals. The term “patient” is intended to denote amammalian individual, and is so used throughout the specification and inthe claims. The primary applications of this invention involve humanpatients, but this invention may be applied to laboratory, farm, zoo,wildlife, pet, sport or other animals.

[0285] Melanocortin receptor-specific compounds of this invention thatare MC1-R specific can be used as chemoprevention agents againstsun-induced, such as by UV radiation, neoplastic activity in human skin.MC1-R agonist compounds of this invention may be employed to stimulateepidermal melanocytes to produce melanin as well as to convertpheomelanin to eumelanin. Eumelanin, which is dark brown or blackpigmentation, is considered more photo-protective than pheomelanin,which is yellow or red pigmentation. The process of melanogenesis isbelieved to involve stimulation of MC1-R in epidermal melanocytes,thereby mediating the stimulation of tyrosinase enzymes within thesepigment cells, inducing the conversion of tyrosine to dopa and thenthrough dopaquinone to eumelanin. Sun tanning due to direct sun exposureis proposed to result from the same pathway by local production ofmelanotropic peptide from a POMC gene in the epidermis. Thus stimulationof eumelanin production and conversion of pheomelanin to eumelanin maybe a desirable chemoprevention modality in blocking sun- or UV-inducedneoplastic activity in skin. A potent, high-affinity and highlyselective MC1-R agonist peptidomimetic compound of this invention canaccordingly be used as a therapeutic chemoprevention agent for combatingharmful sun or UV exposure that induces neoplastic activity in skinmelanocytes.

[0286] In another embodiment, compounds of this invention that are MC4-Ragonists can be used as a therapeutic agent to modify energy metabolismand feeding behavior, including treatment of pathologic obesity andrelated conditions. Compounds of this invention that are MC4-Rantagonists can be used as a therapeutic agent in eating disorders, suchas treatment of anorexia and cachexia, which is malnutrition and wastingdue to illness. Control centers for eating and satiety reside in thehypothalamus. These responses are determined by diverse hormones andsoluble factors that signal through specific receptors in thehypothalamus. MC4-R is known to be expressed in the brain, andinactivation of this receptor by gene targeting has resulted in micewith a maturity-onset obesity syndrome associated with hyperphagia,hyperinsulinemia and hyperglycemia.

[0287] This invention include compounds that are MC4-R agonists orpartial agonists with demonstrated efficacy, in animal models, inmodifying energy metabolism and feeding behavior, and further includescompounds that are inactive or have no intrinsic activity with respectto MC4-R, but bind MC4-R with high affinity and, in some instances,selectivity, and further have demonstrated efficacy, in animal models,in modifying energy metabolism and feeding behavior. It is hypothesized,without desiring to be bound by theory, that at least some compounds ofthis invention that bind MC4-R with high affinity are neutralantagonists of the inverse agonist AgRP, but independently are inactiveor have no intrinsic activity with respect to MC4-R, and that suchcompounds may be used as a therapeutic agent to modify energy metabolismand feeding behavior, including treatment of pathologic obesity andrelated conditions.

[0288] In yet another embodiment, compounds of this invention can beused as therapeutic agents for treatment of sexual dysfunction,including treatment of both male erectile dysfunction and female sexualdysfunction.

[0289] In yet another embodiment, compounds of this invention may beused as therapeutic agents for treatment of inflammation, includingspecifically MC1-R, MC3-R and MC5-R agonists.

[0290] In yet another embodiment of the invention, compounds of thisinvention that are MC5-R specific can be used as agents to decreasesebum production, and thus may be efficacious in the treatment of acneand related diseases. The compounds for this application may beconveniently formulated for local administration, as through a gel,lotion, cream or other topical formulation.

[0291] The compounds may be formulated by any means known in the art,including but not limited to tablets, capsules, caplets, suspensions,powders, lyophilized forms and aerosols and may be mixed and formulatedwith buffers, binders, stabilizers, anti-oxidants and other agents knownin the art. The compounds may be administered by any systemic orpartially systemic means known in the art, including but not limited tointravenous injection, subcutaneous injection, administration throughmucous membranes, oral administration, dermal administration, skinpatches, aerosols and the like.

[0292] The invention further provides a pharmaceutical composition thatincludes a compound of this invention and a pharmaceutically acceptablecarrier. The compound of this invention may thus be formulated orcompounded into pharmaceutical compositions that include at least onecompound of this invention together with one or more pharmaceuticallyacceptable carriers, including excipients, such as diluents, carriersand the like, and additives, such as stabilizing agents, preservatives,solubilizing agents, buffers and the like, as may be desired.Formulation excipients may include polyvinylpyrrolidone, gelatin,hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodiumchloride or sodium citrate. For injection or other liquid administrationformulations, water containing at least one or more bufferingconstituents is suitable, and stabilizing agents, preservatives andsolubilizing agents may also be employed. For solid administrationformulations, any of a variety of thickening, filler, bulking andcarrier additives may be employed, such as starches, sugars, fatty acidsand the like. For topical administration formulations, any of a varietyof creams, ointments, gels, lotions and the like may be employed. Formost pharmaceutical formulations, non-active ingredients will constitutethe greater part, by weight or volume, of the preparation. Forpharmaceutical formulations, it is also contemplated that any of avariety of measured-release, slow-release or time-release formulationsand additives may be employed, such that the dosage may be formulated soas to effect delivery of a compound of this invention over a period oftime.

[0293] The compounds of this invention may be in the form of anypharmaceutically acceptable salt. Acid addition salts of the compoundsof this invention are prepared in a suitable solvent from the compoundand an excess of an acid, such as hydrochloric, hydrobromic, sulfuric,phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonicacids. The acetate salt form is especially useful. Where the compoundsof this invention include an acidic moiety, suitable pharmaceuticallyacceptable salts may include alkali metal salts, such as sodium orpotassium salts, or alkaline earth metal salts, such as calcium ormagnesium salts.

[0294] The compounds and pharmaceutical compositions of this inventionmay be administered by injection, which injection may be intravenous,subcutaneous, intramuscular, intraperitoneal or by any other means knownin the art. In general, any route of administration by which thecompounds of this invention are introduced across an epidermal layer ofcells may be employed. Administration means may include administrationthrough mucous membranes, buccal administration, oral administration,dermal administration, inhalation administration, nasal administrationand the like. The dosage for treatment is administration, by any of theforegoing means or any other means known in the art, of an amountsufficient to bring about the desired therapeutic effect.

[0295] Therapeutically Effective Amount. In general, the actual quantityof compound of this invention administered to a patient will varybetween fairly wide ranges depending upon the mode of administration,the formulation used, and the response desired. This may readily bedetermined by one of ordinary skill in the art through means such aspharmacokinetic studies, plasma half-life studies, dose escalationstudies, and the like. The dosage for treatment is administration, byany of the foregoing means or any other means known in the art, of anamount sufficient to bring about the desired therapeutic effect. Thus atherapeutically effective amount includes an amount of a compound orpharmaceutical composition of this invention that is sufficient toinduce the desired therapeutic effect.

[0296] The compounds of this invention are highly active. For example,the compound can be administered at 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50,100, or 500 μg/kg body weight, depending on specific compound selected,the desired therapeutic response, the route of administration, theformulation and other factors known to those of skill in the art.Conventional dose response studies and other pharmacological means maybe employed to determine the optimal dose for a desired effect with agiven compound, given formulation and given route of administration.

[0297] Combination Therapy and Sexual Dysfunction. It is also possibleand contemplated to use the compounds of this invention in combinationwith other drugs or agents for treatment of sexual dysfunction. Theseother drugs and agents may include melanocortin receptor-specific agentsthat induce erectile activity, including specifically MC3-R and MC4-Ragonists, phosphodiesterase-5 inhibitors, testosterone, prostaglandinand the like. In a preferred embodiment of the invention, compounds ofthe invention are used in combination with a therapeutically effectiveamount of a cyclic-GMP-specific phosphodiesterase inhibitor or analpha-adrenergic receptor antagonist. Similarly, the compounds of thisinvention may be used in combination with any known mechanical aids ordevices.

[0298] The present invention thus provides methods of treating sexualdysfunction, the methods comprising the step of administering to thepatient having or at risk of having sexual dysfunction a therapeuticallyeffective amount of a compound of this invention in combination with atherapeutically effective amount of a second sexual dysfunctionpharmaceutical agent. The compound of this invention may be administeredsimultaneously with, prior to or subsequent to administration with atherapeutically effective amount of a second sexual dysfunctionpharmaceutical agent. Preferably the compound of this invention isadministered within one hour, preferably within less than one-half hour,of administration of a therapeutically effective amount of a secondsexual dysfunction pharmaceutical agent. However, for certain forms ofcombination therapy, such as for example in combination with atherapeutically effective amount of a hormone or hormone-related sexualdysfunction pharmaceutical agent, the hormone or hormone-related sexualdysfunction pharmaceutical agent may be administered on an independentschedule, such that there is no set or specific temporal relationshipbetween administration of the compound of this invention and the hormoneor hormone-related sexual dysfunction pharmaceutical agent. Thus, forexample, the hormone or hormone-related sexual dysfunctionpharmaceutical agent may be administered on a daily or other dose, or bymeans of patches or other continuous administration schedules, withadministration of the compound of this invention when desired or neededby the patient.

[0299] The present invention thus provides methods of treating sexualdysfunction, the methods comprising the step of administering to apatient having or at risk of having sexual dysfunction a therapeuticallyeffective amount of a compound of this invention in combination with acompound that is a melanocortin receptor agonist.

[0300] The present invention further also provides methods of treatingsexual dysfunction, the methods comprising the step of administering toa patient having or at risk of having sexual dysfunction atherapeutically effective amount of a compound of this invention incombination with a compound that is a melanocortin receptor agonist andin combination with another compound that is useful in the treatment ofsexual dysfunction.

[0301] In a preferred embodiment of combination therapy the sexualdysfunction is female sexual dysfunction. In an especially preferredembodiment of combination therapy the sexual dysfunction is erectiledysfunction. In a preferred embodiment of the foregoing methods, themelanocortin receptor agonist is an agonist of MC3-R or MC4-R, andpreferably MC4-R. The agonist may be a non-selective MC3-R and MC4-Ragonist.

[0302] The present invention also provides pharmaceutical compositionsthat comprise 1) a compound of this invention and 2) a compound that isa melanocortin receptor agonist. The present invention further providespharmaceutical compositions that comprise 1) a compound of thisinvention; 2) a compound that is a melanocortin receptor agonist; and 3)a third compound useful for the treatment of sexual dysfunction. Thepresent invention further provides pharmaceutical compositions thatcomprise 1) a compound of this invention and 2) a second compound usefulfor the treatment of sexual dysfunction.

[0303] Representative agonists of the melanocortin receptor which are asecond compound useful in combination therapy are disclosed in thefollowing publications, which are incorporated here by reference intheir entirety: M. E. Hadley et al., Discovery and development of thenovel melanogenic drugs, in Integration of Pharmaceutical Discovery andDevelopment: Case Studies, edited by Borschart et al., Plenum Press, NewYork (1998); R. T. Dorr et al., Evaluation of Melanotan-II, ASuperpotent Cyclic Melanotropic Peptide in a Pilot Phase-I ClinicalStudy. Life Sci. 58:1777-1784 (1996); and R. A. H. Adan, Identificationof Antagonists for Melanocortin MC3, MC4, and MC5 Receptors. Eur. J.Pharmacol., 269:331-337 (1994).

[0304] In one embodiment of the composition above, the agonists are MSHincluding a-, A-, and y-MSH and/or ACTH.

[0305] In another embodiment of the composition above, the melanocortinreceptor agonist is Melanotan-II (MT-II). A preferred melanocortinreceptor agonist includes any linear or cyclic melanocortinreceptor-specific agonist peptide disclosed in International ApplicationWO 03/006620 or a metallopeptide disclosed in International ApplicationWO 02/064091. A particularly preferred melanocortin receptor agonist isAc-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)—OH, as disclosed in U.S. Pat.No. 6,579,968. Alternatively, the agonist may be any agonist disclosedin any of the following patents or patent applications: U.S. Pat. Nos.6,534,503, 6,472,398, 6,458,790, 6,410,548, 6,376,509, or 6,350,760;U.S. Published Application Nos. 2002/01.37664, 2002/0004512,2002/0143141, or US 2003/0069169; or International Application No. WO02/18437. The agonist of the melanocortin receptor may preferably beselective for MC4-R.

[0306] In an embodiment of the composition above, the additionalcompounds useful for the treatment of sexual dysfunction are preferablyselected from but not limited to the group consisting of aphosphodiesterase inhibitor; a cyclic-GMP-specific phosphodiesteraseinhibitor; prostaglandins; apomorphin; oxytocin modulators; α-adrenergicantagonists; dopanergic ligands; androgens; selective androgen receptormodulators (SARMs); buproprion; vasoactive intestinal peptide (VIP);neutral endopeptidase inhibitors (NEP); neuropeptide Y receptorantagonists (NPY); and bombesin receptor-3 antagonists.

[0307] In an embodiment of the method and composition, the second sexualdysfunction pharmaceutical agent is testosterone.

[0308] In another embodiment of combination therapy, the second sexualdysfunction pharmaceutical agent is a type V phosphodiesterase inhibitor(PDE-5). For example, the PDE-5 inhibitor may be Viagra®, a brand ofsildenafil, Levitra®, Cialis®, or may be1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1-H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-ethoxy-phenyl]sufonyl)-4-methylpiperazinecitrate salt, as disclosed in U.S. Published Application No.2003/0083228.

[0309] In another embodiment of the composition above, the compounduseful for the treatment of sexual dysfunction is an estrogenagonist/antagonist. In one embodiment, the estrogen agonist/antagonistis (−)-cis-6-phenyl-5-[-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-napth-thalene-2-ol (alsoknown as lasofoxifene) or an optical or geometric isomer thereof; apharmaceutically acceptable salt, N-oxide, ester, quaternary ammoniumsalt; or a prodrug thereof. More preferably, the estrogenagonist/antagonist is in the form of a D-tartrate salt.

[0310] In yet another embodiment of the composition above, the estrogenagonist/antagonist is selected from the group consisting of tamoxifen,4-hydroxy tamoxifen, raloxifene, droloxifene, toremifene, centchroman,idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-napthalen-2-ol,{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiopehn-3-yl]-methanone,EM-652, EM-800, GW 5368, GW 7604, TSE-424 and optical or geometricisomers thereof; and pharmaceutically acceptable salts, N-oxides,esters, quaternary ammonium salts, and prodrugs thereof.

[0311] In yet another embodiment, a compound of this invention may beused in combination with any known mechanical aids or devices.

[0312] The present invention also provides kits for the treatment ofsexual dysfunction (including erectile dysfunction), the kitscomprising: a first pharmaceutical composition including a compound ofthis invention; a second pharmaceutical composition comprising a secondcompound useful for the treatment of sexual dysfunction; and, acontainer for the first and second compositions.

[0313] Female Sexual Dysfunction. The compounds of this invention may beused to treat female Sexual dysfunction as well as male sexualdysfunction. In general, the dosing schedules and closes for females arecomparable to those for males.

[0314] Combination Therapy and Weight Regulation. It is also possibleand contemplated to use compounds of this invention in combination withother drugs or agents for treatment of various weight andfeeding-related disorders. Where the compound is an agonist or partialagonist, the compound may be employed for decreasing food intake and/orbody weight in combination with any other agent or drug heretoforeemployed as a diet aid, or for decreasing food intake and/or bodyweight. Where the compound binds with high affinity and specificity toMC4-R but has no intrinsic activity at MC4-R, the compound may beemployed for decreasing food intake and/or body weight in combinationwith any other agent or drug heretofore employed as a diet aid, or fordecreasing food intake and/or body weight. Where the compound is anantagonist, the compound may be employed for increasing food intakeand/or body weight in combination with any other agent or drugheretofore employed for increasing food intake and/or body weight.

[0315] Drugs that reduce energy intake include, in part, variouspharmacological agents, referred to as anorectic drugs, which are usedas adjuncts to behavioral therapy in weight reduction programs. Classesof anorectic drugs include, but are not limited to, noradrenergic andserotonergic agents. Noradrenergic medications may be described as thosemedications generally preserving the anorectic effects of amphetaminesbut with weaker stimulant activity. The noradrenergic drugs, exceptphenylpropanolamine, generally act through a centrally mediated pathwayin the hypothalamus that causes anorexia. Phenylpropanolamine, a racemicmixture of norephedrine esters, causes a release of norepinephrinethroughout the body and stimulates hypothalamic adrenoreceptors toreduce appetite.

[0316] Suitable noradrenergic agents include, but are not limited to,diethylpropion such as TENUATE™ (1-propanone,2-(diethylamino)-1-phenyl-, hydrochloride) commercially available fromMerrell; mazindol (or5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol) such asSANOREX™ commercially available from Novartis or MAZANOR™ commerciallyavailable from Wyeth Ayerst; phenylpropanolamine (or Benzenemethanol,alpha-(1-aminoethyl)-, hydrochloride); phentermine (or Phenol,3-[[4,5-duhydro-1H-imidazol-2-yl)ethyl](4-methylphenyl)amino],monohydrochloride) such as ADIPEX-P™ commercially available from Lemmon,FASTIN™ commercially available from Smith-Kline Beecham and Ionamin™commercially available from Medeva; phendimetrazine (or(2S,3S)-3,4-Dimethyl-2phenylmorpholine L-(+)-tartrate (1:1)) such asMETRA™ commercially available from Forest, PLEGINE™ commerciallyavailable from Wyeth-Ayerst; PRELU-2™ commercially available fromBoehringer Ingelheim, and STATOBEX™ commercially available from Lemmon;phendamine tartrate such as THEPHORIN™(2,3,4,9-Tetrahydro-2-methyl-9-phenyl-1H-indenol[2,1-c]pyridineL-(+)-tartrate (1:1)) commercially available from Hoffmann-LaRoche;methamphetamine such as DESOXYN™ Tablets ((S)—N,(alpha)-dimethylbenzeneethanamine hydrochloride) commercially availablefrom Abbott; and phendimetrazine tartrate such as BONTRIL™ Slow-ReleaseCapsules (−3,4-Dimethyl-2-phenylmorpholine Tartrate) commerciallyavailable from Amarin.

[0317] Suitable non-limiting serotonergic agents include sibutraminesuch as MERIDIA™ capsules (a racemic mixture of the (+) and (−)enantiomers of cyclobutanemethanamine,1-(4-chlorophenyl)-N,N-dimethyl-(alpha)-(2-methylpropyl)-,hydrochloride, monohydrate) commercially available from Knoll,fenfluramine such as Pondimin™ (Benzeneethanamine,N-ethyl-alpha-methyl-3-(trifluoromethyl)-, hydrochloride) commerciallyavailable from Robbins; dexfenfluramine such as Redux™(Benzeneethanamine, N-ethyl-alpha-methyl-3-(trifluoromethyl)-,hydrochloride) commercially available from Interneuron. Fenfluramine anddexfenfluramine stimulate release of serotonin and inhibit its reuptake.Sibutramine inhibits the reuptake of serotonin, norepinephrine anddopamine, but does not stimulate secretion of serotonin.

[0318] Other serotonergic agents useful with the practice of the presentinvention include, but are not limited to, certain auoretic gene 5HT1ainhibitors (brain, serotonin) such as carbidopa and benserazide asdisclosed by U.S. Pat. No. 6,207,699 which is incorporated herein byreference; and certain neurokinin 1 receptor antagonists and selectiveserotonin reuptake inhibitors including fluoxetine, fluvoxamine,paroxtine, sertraline and other useful compounds as disclosed by U.S.Pat. No. 6,162,805 which is incorporated herein by reference. Otherpotential inhibitors that may be employed include 5HT2c inhibitors.

[0319] Other useful compounds for reducing energy intake include, butare not limited to, certain aryl-substituted cyclobutylalkylamines asdisclosed by U.S. Pat. No. 6,127,424 which is incorporated herein byreference; certain trifluoromethylthiophenylethylamine derivatives asdisclosed by U.S. Pat. No. 4,148,923 which is incorporated herein byreference; certain compounds as disclosed by U.S. Pat. No. 6,207,699which is incorporated herein by reference; certain kainite or AMPAreceptor antagonists as disclosed by U.S. Pat. No. 6,191,117 which isincorporated herein by reference; certain neuropeptide receptor subtype5 as disclosed by U.S. Pat. No. 6,140,354 which is incorporated hereinby reference; and certain alpha-blocking agents as disclosed by U.S.Pat. No. 4,239,763 which is incorporated herein by reference.

[0320] Moreover, several peptides and hormones regulate feedingbehavior. For example, cholecystokinin and serotonin act to decreaseappetite and food intake. Leptin, a hormone produced by fat cells,controls food intake and energy expenditure. In obese persons who arelosing weight without medications, a decrease in weight is associatedwith a decrease in circulating levels of leptin, suggesting its role inweight homeostasis. Obese patients with high leptin levels are thoughtto have peripheral leptin resistance secondary to the down-regulation ofleptin receptors. Non-limiting examples of useful compounds affectingfeeding behavior include certain leptin-lipolysis stimulated receptorsas disclosed by WO 01/21647 which is incorporated herein by reference;certain phosphodiesterase enzyme inhibitors as disclosed by WO 01/35970which is incorporated herein by reference; certain compounds havingnucleotide sequences of the mahogany gene as disclosed by WO 00/05373which is incorporated herein by reference; and certain sapogenincompounds as disclosed by U.S. Pat. No. 4,680,289 which is incorporatedherein by reference.

[0321] Other useful compounds include certain gamma peroxisomeproliferator activated receptor (PPAR) agonists as disclosed by WO01/30343 and U.S. Pat. No. 6,033,656 which are incorporated herein byreference and certain polypeptides such as fibroblast growth factor-10polypeptides as disclosed by WO 01/18210 which is incorporated herein byreference.

[0322] Moreover, monoamine oxidase inhibitors that decrease energyintake or increase energy expenditure are useful with the practice ofthe present invention. Suitable, but non-limiting examples of monoamineoxidase inhibitors include befloxatone, moclobemide, brofaromine,phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine,sercloremine, bazinaprine, lazabemide, millacemide, caroxazone and othercertain compounds as disclosed by WO 01/12176 which is incorporatedherein by reference.

[0323] Certain compounds that increase lipid metabolism are also usefulwith the practice of the present invention. Such compounds include, butare not limited to, useful evodiamine compounds as disclosed by U.S.Pat. No. 6,214,831 which is incorporated herein by reference.

[0324] Nutrient partitioning agents and digestive inhibitors are anotherstrategy in the treatment of obesity by interfering with the breakdown,digestion or absorption of dietary fat in the gastrointestinal tract.Gastric and pancreatic lipases aid in the digestion of dietarytriglycerides by forming them into free fatty acids that are thenabsorbed in the small intestine. Inhibition of these enzymes leads toinhibition of the digestion of dietary triglycerides. Non-limitingexamples include a lipase inhibitor, orlistat, such as XENICAL™ capsules((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S,3S)-*3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl ester) commerciallyavailable from Roche Laboratories and certain benzoxazinone compounds asdescribed by WO 00/40247 which is incorporated herein by reference.

[0325] Agents that increase energy expenditure are also referred to asthermogenic medications. Non-limiting examples of suitable thermogenicmedications include xanthines, such as caffeine and theophylline,selective P-3-adrenergic agonists for example certain compounds in U.S.Pat. No. 4,626,549 which is incorporated by reference herein, andα-2-adrenergic and growth hormones compounds as described in U.S. Pat.Nos. 4,937,267 and 5,120,713 which are incorporated by reference herein.

[0326] Generally, a total dosage of the above-described obesity controlagents or medications, when used in combination with a compound of thisinvention can range from 0.1 to 3,000 mg/day, preferably from about 1 to1,000 mg/day and more preferably from about 1 to 200 mg/day in single or2-4 divided doses. The exact dose, however, is determined by theattending clinician and is dependent on such factors as the potency ofthe compound administered, the age, weight, condition and response ofthe patient.

[0327] Agents or drugs employed for increasing food intake and/or bodyweight include appetite stimulants such as megastrol acetate,adrenocorticoids such as precinisoine and dexamethanasonecyproheptidine, serotonergic drugs such as fenfluramine, neuropeptide Y,and androgen antagonists such as flutamide, nilutamide, and zanoterone.

[0328] Compounds of the Invention. As discussed hereafter in thesynthetic schemes, one preferred method of making the compounds of theinvention includes synthesis of a linear intermediate composed of chiralbuilding blocks such as amino acid residues or derivatives, whichintermediate includes the R₁ group and an R₂ group, and one of or, ifprovided, both an R₄ and R₅ group, as shown below. The linearintermediate is then cyclicized, and other groups, such as R₃, are thenadded. Thus in this embodiment R₁ and R₄ can be considered to be aminoacid side chain moieties, as defined above. In other of the syntheticschemes, the linear intermediate includes the R₂ group, and one of R₄ orR₅, with the R₁ group synthetically added post-cyclization. In thesynthetic methods the R₃ group is an amino acid residue or derivative,optionally with an amine capping group, second amino acid residue orderivative, or second amino acid residue or derivative and amine cappinggroup. It may thus be seen that the compounds of the invention may beconsidered as a 6-membered ring compound of the formula:

[0329] wherein:

[0330] X is CH₂, C═O or C═S;

[0331] R₁ is an amino acid side chain moiety including at least onecarbocyclic aromatic or non-aromatic ring or heterocyclic aromatic ring,and in a preferred embodiment includes a substituted or unsubstitutedphenyl, naphthyl or indole group;

[0332] R₂ is an amino acid side chain moiety with at least oneheteroatom cationic center, hydrogen bond donor or hydrogen bondacceptor, wherein the least one heteroatom is nitrogen or oxygen;

[0333] R₃ includes at least one amino acid residue with at least onecarbocyclic aromatic ring and in a preferred embodiment, includes asubstituted or unsubstituted phenyl or naphthyl group; and

[0334] At least one of R₄ and R₅ is R₂ or a C₁ to C₆ aliphatic linear orbranched chain.

[0335] It may readily be seen that the foregoing description issimplified, in that at each of R₂, R₄ and R₅ there is assumed to furtherbe a hydrogen, atom bound to the respective ring carbon.

[0336] Thus, by way of example, R₁ can be an amino acid side chainmoiety, including but not limited to one of the following:

[0337] In any of the foregoing, it is understood that any ring may besubstituted with one or more ring substitutents, such as hydroxyl,halogen, sulfonamide, alkyl or aryl groups attached directly or throughan ether linkage.

[0338] Similarly, R₂ may be an amino acid side chain moiety, includingbut not limited to one of the

[0339] —(CH₂)₄—NH₂,

[0340] —(CH₂)₃—NH—C(═O)—CH₃,

[0341] —(CH₂)₃—NH—C(═O)—O—CH₃,

[0342] —(CH₂)₂—NH—C(═NH)—NH₂,

[0343] —(CH₂)₂—NH—C(═O)—NH₂,

[0344] —(CH₂)₄—NH—C(═O)—H,

[0345] —(CH₂)₄—NH—C(═O)—CH₃,

[0346] —(CH₂)₃—NH—C(═O)—NH—CH₃,

[0347] —(CH₂)₃—NH—S(O₂)—NH₂,

[0348] —(CH₂)₃—NH—S(O₂)—CH₃,

[0349] —(CH₂)₃—NH₂,

[0350] —(CH₂)₂—C(═O)—NH₂,

[0351] —(CH₂)₃—NH—C(═NH)—NH—CH₃,

[0352] —(CH₂)₃—NH—C(═NH)—NH—CH₂—CH₃,

[0353] —(CH₂)₃—NH—C(═NH)—NH—CH₂—CH₂—CH₃,

[0354] —(CH₂)₃—NH—C(═NH)—NH—CH—(CH₃)₂,

[0355] —(CH₂)₃—NH—C(═NH)—NH₂,

[0356] —(CH₂)₄—NH—C(═O)—NH₂,

[0357] —(CH₂)₄—NH—C(═NH)—NH₂,

[0358] Particularly preferred are side chains of arginine, lysine andornithine, including derivatives of arginine, lysine and ornithine.

[0359] R₃, which includes least one amino acid residue with at least onecarbocyclic aromatic ring, may be of any of the formulas -A₁, -A₁-cGp,-A₁-A₂ or-A₁-A₂-cGp, where A₁ is an amino acid with an aromaticcarbocyclic ring, A₂ is an L-amino acid, and cGp is an amine cappinggroup. Thus for example it can be seen that the following compounds arecontemplated and included within the invention:

[0360] In a preferred embodiment, A₁ is a D-amino acid with an aromaticcarbocyclic ring. Thus A₁ may be a D-isomer of Phe, Phe(2-Cl),Phe(4-Cl), Phe(2,4-diCl), Phe(2,4-diF), Phe(3,4-diCl), Phe(4-NO₂),Phe(4-Me), Phe(4-Phenyl), HPhe, Phe(4-F), Phe(4-Br), Phe(4-CF₃),Phe(3,4-diF), Phe(4-I), Phe(2-Cl, 4-Me), Phe(2-Me, 4-Cl), Phe(2-F,4-Cl), Phe(2,4-diMe), Phe(2-Cl, 4-CF₃), or Phe(3,4-di-OMe).Alternatively, A₁ may be a D-isomer of Pgl, Trp, Nal 1, Nal 2, Bip, Dip,Bpa, Ser(Bzl), Ser(2-Naphthyl), Ser(Phenyl), Ser(4-Cl-Phenyl),Ser(2-Cl-Phenyl), Lys(Z), Lys(Z-2′Br), Lys(Bz), Thr(Bzl), Tic, Tiq,Cys(Bzl), Tyr(2,6-DiCl-Bzl) or Tyr(Bzl). A₂, where provided, can be anL-isomer of Abu, 2-Abz, 3-Abz, 4-Abz, Achc, Acpc, Aib, Amb, Arg(Tos),Asp(anilino), Asp(3-Cl-anilino), Asp(3,5-diCl-anilino), 11-Aun, AVA,Beta-hHyp(Bzl), Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA, GBzA, B-Gpa,GVA(CI), His, hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp,2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr,Sar, Tle, Tiq, Atc, Igl, Hyp(O-2-Naphthyl), Hyp(O-Phenyl), 2-Aic, Idc,1-Aic, Beta-homoSer(Bzl), Ser(2-Naphthyl), Ser(Phenyl),Ser(4-Cl-Phenyl), Ser(2-Cl-Phenyl), Thr(Bzl), Tic, Beta-homoThr(Bzl),Thr(2-Naphthyl), Thr(Phenyl), Thr(4-Cl-Phenyl), Thr(2-Cl-Phenyl), Nle,Leu, Ile, Val or Beta-Ala. The amine capping group cGp, where provided,can be methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl,pentyl, hexyl, allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl,propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl,cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx,Amc, 8-Aoc or polyethylene glycol.

[0361] Modulation of functional activity of the compounds of thisinvention. The efficacy and functional activity of compounds of thisinvention can be modulated by selection of the linker units and othersubstituents, such as R₄ and/or R₅ groups, which influence theconformational biasness of R₁ and R₃groups. Efficacy and functionalactivity may be determined by any number of means, such as assaying thestimulation of adenyl cyclase in a cAMP assay as hereafter described.

[0362] For example, the chemical nature of either or both the L₁ or L₃linker units, and the incorporation of a substituent at one or morespecific R_(4a), R_(4b), R_(5a) or R_(5b) positions, can changeotherwise identical compounds from a partial agonist to a full agonistas determined by adenyl cyclase assays in an hMCR-4 transfected HEK cellsystem. The nature and character of these changes is described, in part,in the following discussion.

[0363] A commercially available computer based molecular modelingsoftware system, such as Alchemy (Tripos), can be used to study theconformational dynamics within the compounds of this invention. Studiesusing such a molecular modeling software system can explain, in part,the effect of changes such as the chemical nature of either or both theL₁ or L₃ linker units or the incorporation of a substituent at one ormore specific R_(4a), R_(4b), R_(5a) or R_(5b) positions on biologicalactivity.

[0364] A piperazine ring can exhibit conformational dynamics betweenchair and boat conformations, with twisted chair and twisted boatconformations being special cases. In the following discussion, chairand boat conformations are used for purposes of illustration. Assume apiperazine, where X is CH₂, and a conventional ring atom numberingsystem as follows:

[0365] As may readily be seen, both the 1 and 4 position nitrogens aresubstituted with an R group. As a direct result thereof, theconformation of the ring is biased toward a chair conformation, becausethis conformation offers a very low likelihood of steric interactionsinvolving aromatic R₁ and R₃ groups. This may be seen in the followingillustration, wherein the equatorial placement of R₁ and R₃ in the ChairForm results in a conformationally preferred structure, while the closeproximity of the ring nitrogens with R₁ and R₃ groups in the Boat Form(indicated by the double arrow) make the Boat Form conformationallydisfavored.

[0366] Furthermore, the nature of the 1, 4 ring nitrogens, and resultingbond angles, is determined by the nature of the L₁ and L₃ linkers. Forexample, both nitrogens are in the sp³ configuration if L₁ and L₃ are ofthe (CH₂)_(y) type. In this case, the R₁ and R₃ groups orient asequatorial groups on the chair configuration and have a high degree ofconformational freedom in space due to rotational freedom of C-C singlebonds in these groups as shown:

[0367] On the other hand both nitrogens exist in the sp² configurationif L₁ and L₃ have, for example, an initial carbonyl group, such as alinker unit of the —C(═O)-(CH₂)_(y)— type. In this instance, thecarbonyl groups of the ring nitrogen amide functions necessarily existin one of two rigid forms, similar to cis or trans amide forms. Thisspecific orientation of the carbonyl groups in turn restricts theorientation of the J and Q groups. Therefore, where L₁ and L₃ include aninitial carbonyl group, the R₁ and R₃ groups have conformationalorientations that are different from those in compounds without ringnitrogen amide functions, as shown below:

[0368] The inventors have surprisingly and unexpectedly found thatselective orientation of the R₁ group in compounds of this invention, bythe means discussed above, causes a shift or change in efficacy, such asdetermined by functional activity in an adenyl cyclase cell assay, butwithout significantly influencing receptor binding affinity. Forexample, compounds described herein where L, is attached to the ringnitrogen through an amide bond are full agonists with intrinsic activityat MC4-R ranging from 80 to 100% (see the compounds of Examples 38, 42,43, 44 and 45). However, compounds described herein where L₁ is attachedthrough an ethylene group are antagonists or partial agonists withsignificantly lower intrinsic activity, or have no intrinsic activity,either with or without loss of affinity for MC4-R (see the compounds ofExamples 1, 2, 3, 4, 7 and 8).

[0369] The substituents at position 5 and 6 of the piperazine ring alsohave a significant influence on the orientation of the R₁ and R₃ groups.For example an R₄ group in the general structure of this inventioninfluences the spatial preference of the R₃ group, and likewise an R₅group influences the spatial preference of the R₁ group. The majorinfluence of these groups on biological activity is seen in astereo-specific manner. For example, the presence of an R₅ substituent,such as methyl or isobutyl, in an (S)-configuration cause severe stericconstraint on the J group in compounds where L₁ is a —(CH₂)_(y)— linkerunit. This is because both J as well as the (S)-configuration of the R₅group are positioned in a close chemical space. Steric hindrance betweenthese two groups causes perturbations in the overall orientation of theR₁ group, resulting in a structure that is less conducive to receptoraffinity and functional efficacy of the compounds. Typically, a 5-15fold loss of MC4-R affinity has been observed. Similarly, in compoundswhere L₁ is a —C(═O)-(CH₂)_(y)— linker, the incorporation of an(S)-configuration of the R₅ group causes the amide carbonyl to positionaway from the R₅ group, again with a similar potential of stericinteraction with J group. However, positioning of the L₁ carbonyltowards an (S)-configuration of the R₅ group is not possible due tosevere steric interactions between these groups. These three situationscan be shown as:

[0370] By contrast, incorporation of an R₅ substituent, such as methylor isobutyl, in an (R)-configuration positions the R₅ group away fromthe R₁ group. Since there is no perturbation in the positioning of R₁group, this causes no change in MC4-R receptor affinity and selectivity.These structures are shown as follows:

[0371] Incorporation of an R₄ substituent, such as methyl or isobutyl ineither the (R)- or (S)-configuration at the position 6 of the piperazinering cause severe steric constraint on the Q group in compounds where L₃includes a carbonyl, such as a —C(═O)-(CH₂)_(y)— linker. This is becausethe spatial orientation of Q is already influenced by the presence of anR₂ group at the position 2 of the piperazine ring. Furthermore, the(S)-configuration R₂ and (R)-configuration R₄ groups are axiallylocated. These groups have 1,3-diaxial steric interactions that distortthe chair conformer of the piperazine ring. The R₄ group in itsequatorial (S)-configuration form causes severe steric interaction withthe carbonyl of the L₃ linker, as well as the Q group when L₃ is alinker unit such as —(CH₂)_(y)—. Therefore, incorporation of an R₄ groupin either sterochemical orientation leads to compounds that havesomewhat weaker receptor affinity (typically a 5-7 fold decrease hasbeen observed). These three situations can be shown as:

[0372] It is evident from the foregoing that the incorporation of R₄and/or R₅ groups can be employed to modify the functional efficacy ofthese high-affinity melanocortin compounds. These findings may be used,as described herein, to develop compounds that are agonists, weakpartial agonists, mixed agonist-antagonists, antagonists or have nointrinsic activity, and which have utility as agents for modulation ofenergy homeostasis and feeding responses in mammals.

[0373] Steric interaction may be shown by reference to FIG. 1, showingthe structure of a hypothetical compound wherein R₁ and R₃ are eachphenylacetyl, R₂ is (S)-3-aminopropyl, and R₅ is (S)-isobutyl (FIG. 1A)or (R)-isobutyl (FIG. 1B). As may be seen from FIG. 1, there issignificant steric interaction with (S)-isobutyl (FIG. 1A) where L₁includes a carbonyl, but not with (R)-isobutyl.

[0374] Compounds which bind with high affinity, but which have low or noinstrinsic activity, are illustrated by compounds of the followinggeneral structure which are disclosed herein.

Ratio Intrinsic MC1-R MC3-R MC4-R MC5-R (MC1-R/ efficacy Ex. R₅ R₄ Ki(nM) MC4-R) MC4-R — H H 1198 97 3 259 399 37% 1 H (R)-CH₃ 1309 366 15727 87 3% 4 H (S)-CH₃ 3185 551 21 602 152 11% 2 (R)-CH₃ H 1134 95 2 362567 3% 3 (S)-CH₃ H 673 362 14 723 48 6% 8 (R)-iso- H 1364 87 4 160 3410% Butyl 7 (S)-iso- H 5895 495 48 695 123 4% Butyl

[0375] The initial compound, wherein R₅ and R₄ are H, is disclosed asExample 129 in PCT/US02/25574, entitled Peptidomimetics of BiologicallyActive Molecules, filed on Aug. 12, 2002, and incorporated herein byreference. In the foregoing table, intrinsic efficacy or activity lessthan about 10% is not distinguishable from no intrinsic activity. Thus,for example, the compound of Example 8 binds with high affinity (4 nM)at MC4-R, but has no intrinsic activity. The compound of Example 8 isaccordingly inactive as to MC4-R in terms of agonist/antagonist statuswith respect to NDP-α-MSH.

[0376] Synthetic Schemes. Distinct and separate methods for synthesis ofpiperazines and ketopiperazines are required. In many synthetic schemes,piperazine molecules as described herein cannot be obtained fromketopiperazine molecules or synthetic schemes as described herein. Oneobvious limitation to employing ketopiperazine synthetic schemes tosynthesize piperazine molecules is that the presence of other reactivegroups, such as amide, halogen and aromatic functional groups, caninterfere with the process of reducing a ketopiperazine to a piperazine.Thus separate and different methods for the synthesis of piperazineswere developed and are disclosed herein. Similarly, separate methods forthe synthesis of ketopiperazines were also developed and are disclosedhere.

[0377] One general strategy for either class of compounds includesdeveloping a linear intermediate using chiral building blocks such asamino acid derivatives. The linear intermediate can be cyclized using aMitsunobo reaction strategy (Mitsunobo, O. The use of diethylazodicarboxylate and triphenylphosphine in synthesis and transformationof natural products. Synthesis 1:1-28 (1981)), or by spontaneouscyclization through reactive groups such as a reaction between an amineand an aldehyde functional group or an amine and an ester functionalgroup. In these cyclizations, the driving force for intramolecularreaction versus intermolecular reaction is the thermodynamically favoredreaction forming a six-membered ring structure.

[0378] Scheme 4 presented hereafter is an example of a Mitsunoboreaction mediated cyclization. This methodology incorporates conditionsthat do not involve inversion or racemization of chiral centers, otherthan inversion of the chiral center on the carbon to which an —OH groupis attached.

[0379] The methods disclosed herein thus allow for the synthesis ofpiperazine as well as ketopiperazine molecules with the diversefunctionalities disclosed herein. Certain of the schemes further providea facile approach to obtain compounds that differ at R₃ since this groupis introduced after the cyclic intermediate has been synthesized.

[0380] The piperazine compounds of the invention have threestereocenters, such that at each of three distinct carbon atoms themolecule can assume any permissible sterochemical configuration, suchthat eight distinct stereo configurations (2^(n) where n is 3) are bothpossible and contemplated in this invention. Thus the invention includescompounds with stereo configurations as set forth below (where X is CH₂or C═O). It is further understood that for the R₂, R₄ and R₅ positions,as heretofore defined, where a group other than hydrogen is provided forsuch position, that the position includes such group in one of R_(xa) orR_(xb), and hydrogen in the remaining of R_(xa) or R_(xb). Thus, forexample, R₂ may be in either the R_(2a) or R_(2b) position, with theremaining position being hydrogen. In one embodiment, R_(2a) is—(CH₂)_(y)—NH—C(═NH)—NH₂ and R_(2b) is hydrogen, or vice versa, and soon. It may thus be seen that all possible stereochemical configurationsare included within the disclosure of this invention.

[0381] Synthesis of Dipeptide (1-2): The dipeptide (1-2) synthesized inScheme 1 employs an amino alcohol derivative of a suitableomega-protected alpha omega amino acid. This omega protecting group isorthogonal to the N-Prt group, such that one protecting group can beremoved in the presence of the other. 7.8 mL (56 mmol, 1.35 equiv) ofTEA was added to a solution of 40 mmol of protected amino acid (1.1) in200 mL dry THF, kept at −20° C. under N₂, followed by the slow additionof 7.2 mL (55 mmol, 1.35 equiv) of IBCF. The reaction mixture wasstirred for 5 minutes. 9.4 g (60 mmol, 1.5 equiv) of serine methyl esterhydrochloride or an amino alcohol derivative was added, followed by 8.4mL (60 mmol, 1 equiv) of TEA, keeping the temperature below −20° C. Thereaction mixture was stirred for 30 minutes at −10° C., and then allowedto warm to room temperature. 50 mL of 1 N hydrochloric acid was added,and the layers separated. The organic layer was concentrated,redissolved in 150 mL of EtOAc, and washed with 2×50 mL of 1 Nhydrochloric acid, and 1×50 mL saturated sodium bicarbonate solution.The organic layer was dried over magnesium sulfate and concentrated. Thedipeptide (1-2) was purified by silica gel chromatography as necessary.

[0382] Alternate Synthesis of Dipeptide (1-2): The dipeptide can also beprepared by any common peptide synthesis protocol, such as for exampleusing HBTU as the coupling reagent. To a solution of 14.3 mmol ofprotected amino acid (1-1) in 30 mL of dry dimethylformamide (DMF), keptat room temperature under N₂, was added 5.44 g (14.3 mmol, 1 equiv) ofHBTU, followed by 7.5 mL (43.1 mmol, 3 equiv) of diisopropylethyl amine(DIEA). The solution was stirred for 5 minutes, and then 2.5 g (16.1mmol, 1.1 equiv) of serine methyl ester hydrochloride was added in oneportion. The solution was stirred at room temperature for 1 hour,diluted with 100 mL of diethyl ether, and washed with 2×50 mL of 1 Nhydrochloric acid. The organic layer was dried over magnesium sulfate,and the dipeptide (1-2) purified by silica gel chromatography asnecessary.

[0383] Synthesis of ketopiperazine (1-3): To a solution of 5.75 mmol ofdipeptide (1-2) in 40 mL of dry DCM, kept at −20° C. under N₂, was added1.0 mL (7.5 mmol, 1.3 equiv) of TEA, followed by the slow addition of530 μL (6.9 mmol, 1.2 equiv) of methanesulfonyl chloride, keeping thetemperature below −10° C. The mixture was stirred at −10° C. for 15minutes, and then allowed to warm to room temperature. It was stirred atroom temperature until HPLC showed the reaction was completed. Thereaction mixture was then concentrated and partitioned between 25 mL ofether and 25 mL of water. The organic layer was washed with 1×25 mL ofwater, dried over magnesium sulfate, and concentrated. The product (1-3)was purified by silica gel chromatography as necessary.

[0384] Synthesis of piperazine (14): To a solution of 2.9 mmol ofketopiperazine (1-3) in 7 mL of dioxane, kept at room temperature underN₂, was added 550 mg (14.5 mmol, 5 equiv) of sodium borohydride,followed by the slow addition of a solution of 820 mL (14.3 mmol, 5equiv) of acetic acid in 2 mL of dioxane, and the suspension was thenrefluxed under N₂ for 4 hours. The reaction mixture was cooled to roomtemperature, and then quenched by the slow addition of 1 N hydrochloricacid. The reaction mixture was diluted with 25 mL of EtOAc and 15 mL ofwater. The layers were separated, and the organic layer was dried overmagnesium sulfate. The product (14) was purified by silica gelchromatography as necessary.

[0385] Synthesis of functionalized piperazine (1-5): The secondary aminefunctionality of piperazine (14) was reacted with a carboxylic acidderivative of a desired R₁ group (J-COOH) to establish an amide bond.Well-established standard methods of peptide synthesis can be employed.Alternatively, N-functionalization can also be achieved by treating abromo or iodo derivative of an R₁ group (J-Br) with functionalizedpiperazine.

[0386] Synthesis of functionalized piperazine (1-6): The ring N-Prtgroup from compound (1-5) is removed and the free amine treated withQ-COOH or a corresponding Q-bromide to obtain 1-6.

[0387] Synthesis of fully functionalized piperazine (1-7, and 1-8): TheNH-Prt′ group from the functionalized piperazine (1-6) is removed togive 1-7. The amine function of 1-7 can further be alkylated,guanidinated or acetylated using standard procedures to give compoundsof the general structure 1-8. Alkylation can be accomplished by areductive amination reaction with an aldehyde (for example,formaldehyde) under the conditions described in synthesis of 34, usingalkyl bromide (for example, CH₃—Br), or acylation using a carboxylicacid (CH₃—COOH), with guanidation using triphenylphorphine, DIAD, and1,3-Bis(tert-butoxycarbonyl)guanidine as reagents followed by removal ofBoc groups as described in Scheme 5. A guanidation reaction can also beperformed using 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea(1.1 equiv) and silver nitrate (1.1 equiv) and NMM (2.2 equiv) asreagents in acetonitrile as discussed in Scheme 4.

[0388] Synthesis of functionalized ketopiperazines (2-2 and 2-3): TheNH-Prt′ group in ketopiperazine (1-3) is removed and the resulting amineis processed further to introduce an R₃ group as generally described forthe synthesis of substituted piperazine (1-6) in Scheme 1. The aminefunction of 2-2 can be introduced to produce compound 2-3 using asimilar approach as described for the conversion of 1-7 to 1-8 in Scheme1.

[0389] To a solution of J-COOH (e.g., naphthylacetic acid) and HOAt (1equiv) in dry N,N-dimethylformamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1 equiv).After the mixture was stirred at room temperature for one-half hour, achiral amino alcohol (e.g., (R)- or (S)-1-amino-2-propanol or (R)- or(S)-2-amino-1-propanol, affording a methyl group at R₅ or R₄,respectively) (1 equiv) was added. The reaction was continued for 16hours. The reaction mixture was poured into water and extracted by EtOActwice. The organic layer was washed by 1 N hydrochloric acid twice, 1 Nsodium hydroxide twice, brine and dried over sodium sulfate. Afterevaporation, the product was purified on silica gel column with 10%methanol in methylene chloride.

[0390] To this product (1 equiv) and sodium borohydride (5 equiv) indioxane was added acetic acid (5 equiv) in dioxane slowly. Aftercompletion, the mixture was refluxed for 2 hours. The reaction wasquenched by water. The product was extracted from ether by 1 Nhydrochloric acid. The pH value of the resulting aqueous solution wasadjusted with potassium hydroxide to around 11, and the productextracted by ether three times. The organic layer was dried over sodiumsulfate and the solvent was evaporated. The obtained compound 3-1 wasused for next step reaction without further purification.

[0391] To an N-protected amino acid (3-2) (1 equiv), and N-methylmorpholine (1 equiv) in dry DCM was added TBTU (1 equiv). The mixturewas stirred at room temperature for 30 minutes. A mixture ofN,O-dimethylhydroxyamine hydrochloride (1.5 equiv) and NMM (1.5 equiv)in DCM was stirred for 30 minutes. These two mixtures were combined andstirred at room temperature for 18 hours. The organic solvent wasevaporated and the residue loaded on a flash chromatograph column andeluted with EtOAc/hexane (2/1) to yield an N,O-dimethylhydroxyamideproduct. This product was dissolved in dry THF at 0° C. and LAH (1 M inTHF, 1.2 equiv) was added slowly. After 30 minutes the reaction wasquenched by aqueous potassium hydrogen sulfate (1.2 equiv). THF wasremoved and ether was added. The solution was washed by 1 N HCl (2times), aqueous sodium hydrogen carbonate and brine, and dried oversodium sulfate. The solvent was removed under vacuum to give compound3-3. Compound 3-3 was used for next step reaction without furtherpurification.

[0392] A mixture of compound 3-3 and compound 3-1 was stirred in thepresence of activated 4A molecular sieves (1 g) in dry THF (10% aceticacid) for 1 hour. Sodium cyanoborohydride (1 equiv, 1 M solution in THF)was added to this mixture. After 2 hours, solvent was evaporated and thedesired product (34) was purified on silica gel column.

[0393] Compound 34 was treated with 20% diethylamine in EtOAc for 12hours, with the solvent evaporated to dryness. The residue and TPP (3equiv) was dissolved in dry THF. To this solution was added DIAD (3equiv) in THF slowly at 0° C. The reaction was continued for 16 hours atroom temperature. The product 3-5 was purified by silica gel columnafter evaporation of solvent.

[0394] The R₃ group was introduced in compound 3-5 by coupling it withan appropriate amino acid (2 equiv), such as D-Phe or a ring-substitutedderivative or homolog thereof, by use of HOAt (2 equiv) and DIC (2equiv) in N,N-dimethylformamide solution overnight at room temperature.Flash chromatograph (EtOAc/hexane=2) gave the product with protectinggroups. The Fmoc group was removed by treatment with 20% diethyl aminein EtOAc, and the Boc group was removed by treatment with 30% TFA inmethylene chloride for 1 hour, as applicable to the compounds. The finalpure compounds (3-6) were obtained by purification on HPLC.

[0395] 2-Benzyloxycarbonylamino-5-phthalimido-pentanoic acid (4-1) wassynthesized from a mixture of Z-ornithine (1 equiv).N-carethoxy-phthalimide (1 equiv), and TEA (1.2 equiv) in dry THF andrefluxed overnight. The solvent was evaporated in vacuo, the residuedissolved in EtOAc, and washed successively with 1 N HCl, water, brine,dried (MgSO₄) and evaporated in vacuo to afford the crude product, whichwas used for the next reaction without further purification.

[0396] The crude product (4-1) was dissolved in 5 mL of THF and to thesolution was added NMM (1 equiv). The solution was cooled to −15° C.with a salt-ice bath, and IBCF (1 equiv) added. After 10 minutes, thereaction mixture was filtered to remove formed solid salt. The solid waswashed twice with adequate amounts of THF. The filtrate was cooled to−10° C. and to it was added NaBH₄ (1.5 equiv) in water. The reactionmixture was stirred for another 15 minutes, and then concentrated invacuo. The residue was dissolved in EtOAc and washed successively with10% citric acid, saturated NaHCO₃, H₂O and saturated NaCl, and thendried (MgSO₄) and concentrated in vacuo. The crude product was purifiedwith column chromatography eluted with 1:1 EtOAc:hexanes. The purifiedproduct, [4-Phthalimido-1-hydroxymethyl-butyl]-carbamic acid benzylester (4-2), is obtained as a white solid.

[0397] At -20° C. under N₂ to the suspension of 4-2 and TPP (1.5 equiv)in toluene was added tetrabromocarbon (1.1 equiv) and the reactionmixture stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo and the crude product purified by columnchromatography eluted with hexanes and EtOAc (2:1). The purifiedproduct, [1-Bromomethyl-4-phthalimido-butyl]-carbamic acid benzyl ester(4-3), was obtained as a white solid.

[0398] A mixture of 4-3 and an aminoalcohol (3-1) synthesized accordingto Scheme 3 (2 equiv) in DCM was stirred at 65° C. The solvent wasevaporated and the dried reaction mixture heated at 65° C. for 2 hours.The formed crude product was purified by column chromatography andeluted with hexanes (EtOAc 1:2) to give 44.

[0399] At room temperature under nitrogen a mixture of 4-4 (0.41 mmol)and palladium black (80 mg) in 21 mL of 4% HCHO in methanol is stirredvigorously for 1 hour. The reaction mixture is filtered and the filtrateneutralized with saturated NaHCO₃. The methanol is evaporated and theresidue dissolved in EtOAc and washed successively with saturatedNaHCO₃, water and saturated NaCl, then dried (MgSO₄) and evaporated. Theproduct 4-5 is collected as a white solid.

[0400] At 0° C. under nitrogen to the mixture of 4-5 and TPP (1.5 equiv)in anhydrous THF was added diethyl azodicarbonate (1.1 equiv) inanhydrous THF. After stirring at room temperature for 4 hours, thereaction mixture was evaporated in vacuo and the crude product purifiedby column chromatography. The product 4-6 was obtained.

[0401] To a mixture of 4-6 (1 equiv), a desired carboxylic acid orappropriate protected amino acid residue, including without limitationring-substituted D-Phe analogs and homologs (2 equiv), and HOAt (2equiv) in DMF was added diisopropylcarboimide (2 equiv). The reactionmixture was stirred at room temperature overnight. The solvent wasevaporated in vacuo and the crude product purified by columnchromatography (eluted with hexanes, EtOAc 1:2). The purified product4-7 was obtained as a white solid.

[0402] A solution of 4-7 in 10 mL of 0.2 M hydrazine in methanol wasstirred at room temperature for 19 hours. Mass spectroscopy showed nostarting material left in the reaction mixture. The reaction mixture wasevaporated and co-evaporated three times with methanol and once withEtOAc, then dried under high vacuum for 2 days. The crude product 4-8was used for the next reaction without further purification. 10 mg ofthe crude product 4-8 was treated with 3 mL of 33% TFA in DCM at roomtemperature for 2.5 hours. The solvent was removed by evaporation andthe crude product purified by HPLC (10-90-60, in an acetonitrile-watergradient flow). After lyophilization of the collected fractions, theproduct 4-9 was obtained as white solid.

[0403] Alternatively, the crude product 4-8 was reacted with1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.1 equiv) andsilver nitrate (1.1 equiv) and NMM (2.2 equiv) in 5 mL of acetonitrileat room temperature for 24 hours, followed by evaporation to remove thesolvent and column chromatography purification to produce the 4-10.Product 4-10 was treated with 33% TFA in DCM at room temperature for 2hours and the reaction mixture concentrated and purified with HPLC togive the final compound 4-11.

[0404] To a solution of compound Fmoc-Glutamol(OBut) (5-1) in DCM wasadded 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.1 equiv)in portions. After stirring for 30 minutes at room temperature, thesolution was diluted by ether, followed by addition of 25% sodiumthiosulphate in an aqueous solution saturated with sodium bicarbonate.The mixture was stirred for an additional 5 minutes and the desiredcompound was extracted by EtOAc. The organic layer was washed bysaturated bicarbonate solution, water and subsequently dried overmagnesium sulfate. After evaporation of solvent, compound 5-2 wasobtained for the next step reaction without further

[0405] A mixture of compound 5-2, (R)- or (S)-amino acid methyl ester (1equiv), or another selected amino acid methyl ester, such as an alphaamino acid with its side chain appearing as R₅ in the final compound5-8, and TEA (1 equiv) in the presence of a 4 Å molecular sieve in dryTHF was stirred for two hours. After addition of sodiumtriacetoxyborohydride (1.5 equiv) the mixture was stirred for anadditional 16 hours. The solid was removed by filtration and the productextracted by EtOAc from water. The organic layer was dried over sodiumsulfate. After evaporation of solvent the residue was dissolved in EtOAccontaining 20% diethylamine. The reaction was carried out for 16 hoursand solvent removed under vacuum. The product 5-3 was obtained afterpurification by chromatography.

[0406] To a solution of a desired carboxylic acid (1 equiv), or arelated acid constituting itself as R₁ in the final compound 5-8, andN-methylmorpholine (1 equiv) in DCM at −15° C. was added isopropylchloroformate (1 equiv) slowly. The reaction mixture was stirred for 30minutes and compound 5-3 was subsequently added. After 30 minutes thereaction temperature was raised to room temperature and the mixture wasstirred for 16 hours. The solvent was evaporated and the residue waspurified on column to yield compound 54.

[0407] To the solution of compound 54 in THF was added LAH (in THF, 4.5equiv) slowly. The reaction was conducted at room temperature for 2hours and refluxing temperature for 16 hours. After cooling, thereaction mixture was treated with water, 15% sodium hydroxide andsubsequently water. The white solids were removed by filtration andsolvent was evaporated. The residue contained compound 5-5, which wasused for the next step reaction without further purification.

[0408] Compound 5-5 and N-(benzyloxylcarbonyloxy)succinimide (1.5 equiv)was dissolved in acetonitrile. The mixture was stirred for 16 hours. Thesolvent was evaporated and residue was re-dissolved in methanol. To thissolution was added 1 N sodium hydroxide (1.5 equiv). The mixture wasstirred for additional 16 hours. After evaporation of solvent theresidue was purified on column to yield compound 5-6.

[0409] To a mixture of compound 5-6, triphenylphorphine (3 equiv) and1,3-Bis(tert-butoxycarbonyl)guanidine (3 equiv) in toluene was addedDIAD (3 equiv) slowly at 0° C. The reaction mixture was stirred for 16hours at room temperature. After evaporation of solvent the residue waspurified on a column to give the desired compound. This compound wassubject to treatment with hydrogen in the presence of a catalytic amountof palladium on carbon (10%) in methanol. After 16 hours the solvent wasevaporated and the residue was purified on a column to give compound5-7.

[0410] Compound 5-7 was coupled with desired amino acids (2 equiv) byuse of HOAt (2 equiv) and DIC (2 equiv) in N,N-dimethylformamidesolution overnight at room temperature to introduce the desired R₃moiety in the molecule. Flash chromatograph gave the product withprotecting groups. The Fmoc group was removed by treatment with 20%diethyl amine in EtOAc and the Boc group was removed by treatment with30% TFA in methylene chloride for 1 hour, as applicable to the specificcompounds. The final pure compound (5-8) was obtained by purification onHPLC.

[0411] The alkyl groups on the amino group of D-4-Cl-phenylalaninemoiety in Examples 31, 32, 33 and 34 were were introduced by reductiveamination as described for the synthesis of compound 3-4.

[0412] To a solution of compound 5-3 and TEA (1 equiv) in DCM at 0° C.benzyl chloroformate (1 equiv) was added slowly. The reaction wascarried out overnight. After evaporation of solvent the product waspurified on column to give 6-1.

[0413] Compound 6-1 was dissolved in dry THF, to which borane in THF (1M solution, 5 equiv total) was added. This solution was stirred for 16hours. The reaction was quenched with 1 N HCl and the solution wassubsequently neutralized by 1 N NaOH. The product was extracted by EtOAcand the organic layer was washed by water, brine and dried over sodiumsulfate. The solvent was evaporated and the dried product 6-2 was usedfor next step reaction.

[0414] Compound 6-2 was coupled with desired amino acids (1.5 equiv) byuse of HOAt (1.5 equiv) and DIC (1.5 equiv) in N,N-dimethylformamidesolution overnight at room temperature. Flash chromatograph gave theproduct with protecting groups (6-3).

[0415] To a mixture of compound 6-3, triphenylphorphine (3 equiv) and1,3-Bis(tert-butoxycarbonyl)guanidine (3 equiv) in toluene was addedDIAD (3 equiv) slowly at 0° C. The reaction mixture was stirred for 16hours at room temperature. After evaporation of solvent the residue waspurified on a column to give the desired compound. This compound wassubject to treatment with hydrogen in the presence of a catalytic amountof palladium on carbon (10%) in methanol. After 16 hours the solvent wasevaporated and the residue was purified on a column to give compound6-4. This was reacted in one of the two following different ways to givethe final compound:

[0416] (a) Reaction of compound 6-4 with J-aldehydes: A mixture ofcompound 6-4 and J-aldehyde (1 equiv) in the presence of a 4A molecularsieve in dry THF was stirred for two hours. After addition of sodiumtriacetoxyborohydride (1.5 equiv) the mixture was stirred for anadditional 16 hours. The solid was removed by filtration and the solventwas evaporated. The residue was purified on column to give the desiredcompound with Boc protecting groups.

[0417] (b) Reaction of compound 6-4 with J-carboxylic acids: Compound6-4 was coupled with J-carboxylic acid (1.5 equiv) by use of HOAt (1.5equiv) and DIC (1.5 equiv) in N,N-dimethylformamide solution overnightat room temperature. Flash chromatograph gave the product with Bocprotecting groups.

[0418] In either of the foregoing cases, the compounds with Boc groupswere subjected to treatment with TFA/DCM (50/50) for one hour. Afterevaporation of solvent the final compound 6-5 was purified on HPLC.

[0419] Compound 7-1 is synthesized by the methods described for compound5-3. The starting material is an (R)- or (S)-isomer of Fmoc-alaninol.The aldehyde thus obtained is subsequently reacted with Orn(Boc)-OMeunder reductive amination conditions, and with cyclization givescompound 7-1 after removal of the Fmoc group. Thereafter compound 7-2 issynthesized by a method similar to that described for compound 6-1;compound 7-3 is synthesized by a method similar to that described forcompound 6-2; compound 7-4 is synthesized by a method similar to thatdescribed for compound 6-5; and compound 7-5 is synthesized by a methodsimilar to that described for compound 4-10.

[0420] Compound 7-5 is treated with hydrogen in the presence ofcatalytic amounts of palladium on carbon in a suitable solvent at roomtemperature for 16 hours. After filtration the solvent is evaporated andthe resulting compound is processed to give compound 7-6 in a mannersimilar to that described for synthesis of compound 5-8.

[0421] The resulting compound 7-6 illustrates an alternative route formaking an enantomeric form of the compounds. However, depending onselection of the chiral starting materials, similar results and otherstereoisomers can be obtained by any of the synthetic schemes disclosed.

[0422] To Fmoc-Orn(Boc)—OH and NMM (1 equiv) in dry DCM is added TBTU (1equiv). The mixture is stirred at room temperature for 30 minutes.Separately, a mixture of Orn(Boc)-OMe hydrochloride (1 equiv) and NMM (1equiv) in DCM is stirred for 30 minutes. These two mixtures are combinedand stirred at room temperature for 16 hours. The organic solvent isevaporated and the residue is extracted by EtOAc. The organic layer iswashed by 1 N NaOH, water, 1 N HCl, water, and brine and then dried oversodium sulfate. After removal of the solvent the compound is treatedwith 20% diethyl amine in EtOAc for 16 hours. The solvent is evaporatedand the residue is purified on column to give compound 8-1. Thereafter,compound 8-2 is synthesized by a method similar to that described forcompound 6-2; compound 8-3 is synthesized by a method similar to thatdescribed for compound 6-1; compound 8-4 is synthesized by a methodsimilar to that described for compound 4-10; and compound 8-5 issynthesized by a method similar to that described for compound 7-6.Alternatively, 8-3 can be processed directly to 8-6 as shown to getcompounds that have amino groups instead of guanidines.

[0423] Compound 8-5 and 8-6 thus has two identical R₁ groups, oralternatively has two identical R₃ groups, and further has two identicalR₂ groups. Compounds of Scheme 8 are thus special cases of the generalformula, in which the group corresponding to R₅ is identical to thegroup corresponding to R₂.

[0424] To Fmoc-Glu(Boc)—OH and NMM (1 equiv) in dry DCM is added TBTU (1equiv). The mixture is stirred at room temperature for 30 minutes.Separately, a mixture of Glu(Boc)-OMe hydrochloride (1 equiv) and NMM (1equiv) in DCM is stirred for 30 minutes. These two mixtures are combinedand stirred at room temperature for 16 hours. The organic solvent isevaporated and the residue is extracted by EtOAc. The organic layer iswashed by aqueous sodium bicarbonate, water, 1 N HCl, water, and brineand then dried over sodium sulfate. After removal of the solvent thecompound is treated with 30% diethyl amine in EtOAc for 5 hours. Thesolvent is evaporated and the residue is dissolved in DMF and thesolution is heated at 60° C. for 16 hours. The solvent is evaporated andthe solid is washed by EtOAc. The collected solid 9-1 is dried undervacuum and used for the next step reaction.

[0425] To the solution of 9-1 in DMF was added 4-dimethylaminopyridine(2 equiv) and dibenzyl dicarbonate (2 equiv). The reaction is carriedout for 16 hour at room temperature. After removal of solvent theresidue is purified on silica gel column to give product 9-2.

[0426] Compound 9-3 is synthesized by a method similar to that describedfor compound 6-2.

[0427] Compound 94 is synthesized by a method similar to that describedfor compound 64.

[0428] Compound 9-5 is synthesized by a method similar to that describedfor compound 7-6.

[0429] Alternatively 9-3 can be processed in a manner similar tosynthesis of compound 9-5 from 94 to give 9-6.

[0430] Compounds 9-5 and 9-6 thus has two identical R₁ groups, oralternatively has two identical R₃ groups, at the R₁ and R₃ positions,and further has two identical R₂ groups, at the R₂ and R₅ positions.Compounds of Scheme 9 are thus special cases of the general formula, inwhich the group corresponding to R₅ is identical to the groupcorresponding to R₂.

[0431] To a solution of carboxylic acid and HOAt (1 equiv) in dryN,N-dimethylformamide is added1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1 equiv).After the mixture is stirred at room temperature for half an hour, 1 or2-substituted ethanolamine (1.5 equiv) is added. The reaction iscontinued for 16 hours. The reaction mixture is poured into water andextracted by EtOAc twice. The organic layer is washed by 1 Nhydrochloric acid twice, 1 N sodium hydroxide twice, brine and driedover sodium sulfate. After evaporated the solvent the product (10-1) ispurified on silica gel column with 10% methanol on methylene chloride.

[0432] To compound 10-1 (1 equiv) and sodium borohydride (5 equiv) indioxane is added acetic acid (5 equiv) in dioxane slowly. Aftercompletion the mixture is refluxed for 2 hours. The reaction is quenchedby water. The product is extracted from ether by 1 N hydrochloric acid.The pH value of aqueous solution is adjusted with potassium hydroxide toaround 11 and the product is extracted by ether three times. The organiclayer is dried over sodium sulfate and solvent is evaporated. Theobtained compound 10-2 is used for next step reaction without furtherpurification.

[0433] An N-protected amino acid (1 equiv), HOAt (1 equiv) and DIC (1equiv) in N,N-dimethylformamide solution is stirred for half an hour. Tothis solution is added compound 10-2 and the mixture is stirredovernight. After evaporating solvent, compound 10-3 is obtained bysilica gel column purification.

[0434] The protecting group Prt (Fmoc or Cbz) is removed by either 20%diethyl amine in EtOAc or by hydrogen catalyzed with 10% palladium oncarbon. The resulting compound is dissolved in dry THF withtriphenylphosphine (3 equiv). To this solution is added DEAD (3 equiv)in THF slowly. The reaction is stirred for an additional 12 hours. Afterthe solvent is evaporated the product (10-4) is purified on silica gelcolumn.

[0435] Compound 10-4 is coupled with desired amino acids (2 equiv) byuse of HOAt (2 equiv) and DIC (2 equiv) in N,N-dimethylformamidesolution overnight at room temperature. Flash chromatograph gives theproduct with protecting groups. The Fmoc group is removed by treatmentwith 20% diethyl amine in EtOAc and the Boc group is removed bytreatment with 30% TFA in methylene chloride for 1 hour, as applicableto the compounds. The final pure compound (10-5) is obtained bypurification on HPLC.

[0436] Assays and Animal Models.

[0437] Selected compounds were tested in assays to determine binding andfunctional status, and were tested in animal models of penile erection,feeding behavior and conditioned taste avoidance, as discussed below.The following assays and animal models were employed, with modificationsas discussed in the examples.

[0438] Competitive inhibition assay. A competitive inhibition bindingassay was conducted using membranes prepared from hMC3-R, hMC4-R,hMC5-R, and B-16 mouse melanoma cells (containing MC1-R) using 0.4 nM¹²⁵I-NDP-α-MSH (New England Nuclear, Boston, Mass., USA) in 50 mM HEPESbuffer containing 1 mM MgCl₂, 2 mM CaCl₂, and 5 mM KCl, at pH 7.2. Theassay tube also contained a chosen concentration of the test compound ofthis invention, typically a 1 [M concentration, for determining itsefficacy in inhibiting the binding of ¹²⁵I-NDP-α-MSH to its receptor.Non-specific binding was measured by complete inhibition of binding or¹²⁵I-NDP-α-MbH in the assay with the presence of 1 μM A-MSH.

[0439] Incubation was for 90 minutes at room temperature, after whichthe assay mixture was filtered and the membranes washed three times withice cold buffer. The filter was dried and counted in a gamma counter forremaining radioactivity bound to the membranes. 100% specific bindingwas defined as the difference in radioactivity (cpm) bound to cellmembranes in the absence and presence of 1 μM α-MSH. The cpm obtained inpresence of test compounds were normalized with respect to 100% specificbinding to determine the percent inhibition of ¹²⁵-NDP-α-MSH binding.Each assay was conducted in triplicate and the actual mean values aredescribed, with results less than 0% reported as 0%.

[0440] EC₅₀ determination in functional activity assay. The Ki (nM) ofcertain compounds of the invention were determined. Functionalevaluation of compounds at melanocortin receptors was performed bymeasuring the accumulation of intracellular cAMP in HEK-293 cellsexpressing MC3-R, MC4-R or MC5-R, and in B-16 mouse melanoma cells(containing MC1-R). Cells, suspended in Earle's Balanced Salt Solutioncontaining 10 mM HEPES, pH 7.5, 5 mM MgCl₂, 1 mM glutamine, 0.1% albuminand 0.6 mM 3-isobutyl-1-methyl-xanthine, a phosphodiesterase inhibitor,were plated in 96 well plates at a density of 0.5×10⁵ cells per well.Cells were incubated with the test compounds in the presence or absenceof α-MSH for 1 hour at 37° C. cAMP levels were measured by EIA(Amersham) in the cell lysates. Data analysis and EC₅₀ values weredetermined using nonlinear regression analysis with Prism Graph-Padsoftware.

[0441] Functional status. The agonist/antagonist status with respect toMC₁₋₄, MC4-R, and MC5-R of certain compounds of the invention wasdetermined. Antagonistic activity was determined by measuring theinhibition of α-MSH-induced or NDP-α-MSH-induced cAMP levels followingexposure to the compounds as in the preceding descriptions.

[0442] Penile erection induction. The ability of compounds to inducepenile erection (PE) in male rats were evaluated with selectedcompounds. Male Sprague-Dawley rats weighing 200-250 g were kept on a 12hour on/off light cycle with food and water ad libitum. All behavioralstudies were performed between 10 a.m. and 5 p.m. Groups of 4-8 ratswere treated with compounds at a variety of doses via intravenous (IV)or intracerebroventricuiar (ICV) routes. Immediately after treatment,rats were placed into individual polystyrene cages (27 cm long, 16 cmwide, and 25 cm high) for behavioral observation. Rats were observed for30 minutes IV or 90 minutes ICV, and the number of yawns, grooming boutsand PEs were recorded in 10-minute bins.

[0443] ICV food intake and body weight change. Change in food intake andbody weight was evaluated for selected compounds. Rats with indwellingintracerebroventricular cannulas (ICV rats) were obtained from HilltopLab Animals, Inc. (Scottdale, Pa.). Animals were individually housed inconventional plexiglass hanging cages and maintained on a controlled 12hour on/12 hour off light cycle. Water and powdered (LabDiet, 5P00Prolab RMH 3000) or pelleted (Harlan Teklad 2018 18% Protein RodentDiet) food was provided ad libitum. For 1 week before treatment, 24-hourfood intake and body weight change was recorded to assess a baseline forthe group during vehicle treatment. The rats were dosed ICV with vehicleor selected compounds (1-3 nmol). The changes in body weight and foodintake for the 24 hour period after dosing were determined. The changesin body weight and food intake for the 48 hour period, and in same casesfor 72 hours as well, after dosing were also measured to determinedreversal of changes in body weight and food intake effect back tobaseline.

[0444] IV food intake and body weight change. Change in food intake andbody weight was evaluated for selected compounds. Male Sprague-Dawleyrats were obtained from Taconic (Germantown, N.Y.). Animals wereindividually housed in conventional plexiglass hanging cages andmaintained on a controlled 12 hour on/12 hour off light cycle. Water andpowdered (LabDiet, 5P00 Prolab RMH 3000) or pelleted (Harlan Teklad 201818% Protein Rodent Diet) food was provided ad libitum. For 1 week beforetreatment, 24-hour food intake and body weight change was recorded toassess a baseline for the group during vehicle treatment. The rats weredosed IV with vehicle or selected compounds (0.5-3 mg/kg). The changesin body weight and food intake for the 24 hour period after dosing weredetermined. The changes in body weight and food intake for the 48 hourperiod, and in same cases for 72 hours as well, after dosing were alsomeasured to determined reversal of changes in body weight and foodintake effect back to baseline.

[0445] Behavioral Satiety Sequence. Male Sprague-Dawley rats weremaintained on a restricted 20 g powdered food/day schedule. Food waspresented at the same time during the lights on period dosed with eithersaline or the test compound 2 hours before presentation of food and thestart of observation. Pre-weighed bowls (containing 20 g of food) werepresented and the behavior of the rats was observed for 1 hour.Behavioral observations were divided into 3 categories: Feeding, Active(includes grooming, drinking and sniffing/exploration), and Resting(decreased activity and sleep). The amount of time spent in eachbehavior was recorded. The amount of food intake was determined afterthe observation period.

[0446] Conditioned Taste Avoidance. Male Sprague-Dawley rats wereadapted to a restricted drinking period of 30 minutes/day during lightson and were provided with pelleted chow ad libitum. In laboratoryanimals, administration of LiCl conditions an aversion to the novel andfavorable taste of saccharin (Seeley R J, Blake K, Rushing Pa., BenoitS, Eng J, Woods SC and D'Alessio D: The role of CNS glucagons-likepeptide-1 (7-36) amide receptors in mediating the visceral illnesseffects of lithium chloride. J. Neurosci. 20(4):1616-1621, 2000). Tocondition animals, an injection of LiCl or test compound wasadministered immediately after the initial presentation of a 0.1%solution of saccharin. Two days later, saccharin solution was againpresented and fluid intake was determined. A decrease in drinking thesaccharin solution suggests development of a conditioned taste aversion.

[0447] Determination of mass and nuclear magnetic resonance analysis.The mass values were determined using a Waters MicroMass ZQ deviceutilizing a positive mode. Mass determinations were compared withcalculated values and expressed in the form of mass weight plus one (M+1or M+H).

[0448] Proton NMR data was obtained using a Bruker 300 MHz spectrometer.The spectra were obtained after dissolving compounds in a deuteriatedsolvent such as chloroform, DMSO, or methanol as appropriate.

EXAMPLE 1N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalen-2-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0449] The following compound was synthesized by the method of Scheme 3using 2-naphthylacetic acid as J-COOH, (S)-(+)-1-amino-2-propanol asNH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OH as Prt-NH—C(R₂)—COOH andBoc-D-2,4-dichloro-Phe-OH as Q-COOH. It was tested as described abovewith the results shown. The mass was analyzed as 569.4 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 14 32 95 36 Ki (nM) 1309 36615 727

[0450] In a cAMP assay using MC4-R, at 1 μM concentrations the compoundof Example 1 exhibited no intrinsic activity.

EXAMPLE 2N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0451] The following compound was synthesized by the methods of bothSchemes 3 and 5 using 2-naphthylacetic acid as J-COOH,(R)-(−)-2-amino-1-propanol as NH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OHas Prt-NH—C(R₂)—COOH, D-Alanine methyl ester as NH₂—CH(R₅)—COOCH₃ andBoc-D-2,4-dichloro-Phe-OH as Q-COOH. It was tested as described abovewith the results shown. The mass was analyzed as 569.3 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 20 72 99 65 Ki (nM) 1134 95 2362

[0452] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was an antagonist as to MC4-R.

[0453] In ICV feeding studies at 1 nmol dose levels, a 24 hour change infood intake of 2.6 g, and change in weight of −0.3 g, was observed.

EXAMPLE 3N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0454] The following compound was synthesized by the method of Scheme 3using 2-naphthylacetic acid as J-COOH, (S)-(+)-2-amino-1-propanol asNH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OH as Prt-NH—CH(R₂)—COOH, andBoc-D-2,4-dichloro-Phe-OH as Q-COOH. It was tested as described abovewith the results shown. The mass was analyzed as 569.3 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 6 40 95 425 Ki (nM) 673 36214 723

[0455] In a cAMP assay using MC4-R, at 1 μM concentrations the compoundof Example 3 exhibited no intrinsic activity.

EXAMPLE 4N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-6(S)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0456] The following compound was synthesized by the method of Scheme 3using 2-naphthylacetic acid as J-COOH, (R)-(−)-1-amino-2-propanol asNH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OH as Prt-NH—CH(R₂)—COOH, andBoc-D-2,4-dichloro-Phe-OH as Q-COOH. It was tested as described abovewith the results shown. The mass was analyzed as 569.0 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 3 47 97 64 Ki (nM) 3185 55121 602

[0457] In a cAMP assay using MC1-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 4 exhibited no intrinsic activityat MC1-R and MC5-R, and was a partial agonist at MC4-R.

EXAMPLE 5N-{3-[1-[2(R)-Amino-3-(2-chloro-4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0458] The following compound was synthesized by the methods of bothSchemes 3 and 5 using 2-naphthylacetic acid as J-COOH,(R)-(−)-2-amino-1-propanol as NH₂—CH(R₅)-CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OHas Prt-NH—CH(R₂)—COOH, D-Alanine methyl ester as NH₂—CH(R₅)—COOCH₃ andBoc-D-2-chloro-4-methyl-Phe-OH as Q-COOH. It was tested as describedabove with the results shown. The mass was analyzed as 549.0 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 14 68 99 63 Ki (nM) 907 227 5527

[0459] In a cAMP assay using MC4-R, at 1 μM concentrations the compoundof Example 5 exhibited no intrinsic activity.

[0460] In ICV feeding studies at 1 nmol dose levels, a 24 hour change infood intake of −1.6 g, and change in weight of −3.9 g, was observed.

EXAMPLE 6N-{3-[1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0461] The following compound was synthesized by the methods of bothSchemes 3 and 5 using 2-naphthylacetic acid as J-COOH,(R)-(−)-2-amino-1-propanol as NH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OHas Prt-NH—CH(R₂)—COOH, D-alanine methyl ester as NH₂—CH(R₅)—COOCH₃ andBoc-D-4-chloro-2-methyl-Phe-OH as Q-COOH. It was tested as describedabove with the results shown. The mass was analyzed as 549.0 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 6 74 100 77 Ki (nM) 1052 99 1219

[0462] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC4-R.

[0463] In rat model IV and ICV penile erection induction experiments atdoses ranging from 0.3 to 30 μg/Kg given IV and at 0.01 to 10 nmolegiven ICV, no penile erection response was observed.

[0464] In ICV feeding studies at 1 nmol dose levels, a 24 hour change infood intake of −5.5 g was observed.

[0465] Feeding studies were conducted as described above ICV at a 1nmole dose level, IV at both 1 and 3 mg/Kg dose levels, and IP(intraperitoneal) at 3 mg/kg. Male Sprague-Dawley (8 to 12 per group)were fed powdered chow and water ad libitum, and dosed ICV, IV or IPwith either vehicle or selected compounds with the following results:Difference in Food Intake vs. Vehicle, Grams of Food ICV IV IV IP 1nmole 1 mg/Kg 3 mg/Kg 3 mg/Kg −5.3 0.4 −3.5 −0.7

[0466] In behavioral satiety studies, male Sprague-Dawley rats weremaintained on a restricted food schedule. When food was presented, ratsshowed a sequence of feeding activity followed by increased time spentresting. The compound of Example 6 administered IV 2 hours prior to foodpresentation caused a decrease in food intake and feeding behavior andan earlier onset in resting behavior consistent with a satiety effect(Halford J C, Wanninayake S C and Blundell J E: Behavioral satietysequence (BSS) for the diagnosis of drug action on food intake.Pharmacol. Biochem. Behav. 61(2):159-168, 1998), as shown FIG. 4,showing behavior compared to saline, and FIG. 5, showing total one-hourfood intake in grams. No abnormal behavior was seen.

[0467] In conditioned taste avoidance studies, rats were conditioned toassociate a 0.1% saccharin solution with a dose of either lithiumchloride or the compound of Example 6. Two days later, a 0.1% saccharinsolution was presented again. A decrease in fluid intake suggestsdevelopment of a conditioned taste aversion. As shown in FIG. 7, therewas no conditioned taste avoidance associated with the compound ofExample 6.

[0468] Repeat dosing studies were conducted in C57BL6 mice (n=10 pergroup), housed in a reverse light cycle (on at 12 am off at 12 pm), andweighed daily at 11:00. The compound of Example 6 was diluted in sterilesaline, 0.6 mg/mL and dosed IP at 5 mL/kg at 11:00 am. For BID dosing,drugs were administered at 11:00 am and 4:30 pm. Mice were dosed withthe compound of Example 6 (3 mg/kg) twice a day for the first 3 days andonce per day for the next 4 days. As shown in FIG. 8, which alsoincludes data on the compound of Example 10, mice in growth phaseadministered the compound of Example 6 initiated net wet gain aftercessation of treatment (after day 7), but consistently maintainedaverage weights less than control animals receiving saline.

EXAMPLE 7N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0469] The following compound was synthesized by the method of Scheme 3using 2-naphthylacetic acid as J-COOH, L-leucinol asNH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂-OH as Prt-NH—CH(R₂)—COOH, andBoc-D-2,4-dichloro-Phe-OH as Q-COOH. It was tested as described abovewith the results shown. The mass was analyzed as 611.1 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 4 16 95 28 Ki (nM) 5895 49548 695

[0470] In a cAMP assay using MC1-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 7 exhibited no intrinsic activityat MC4-R, and was a partial agonist at MC1-R and MC5-R.

EXAMPLE 8N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-isobutyl-4-(2naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0471] The following compound was synthesized by the methods of bothSchemes 3 and 5 using 2-naphthylacetic acid as J-COOH, D-Leucinol asNH₂—CH(R₅)—CH(R₄)—OH, D-leucine methyl ester as NH₂—CH(R₅)—COOCH₃,Fmoc-L-Arg(Boc)₂—OH as Prt-NH—CH(R₂)—COOH, and Boc-D-2,4-dichloro-Phe-OHas Q-COOH. It was tested as described above with the results shown. Themass was analyzed as 611.1 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 21 64 99 75 Ki (nM) 1364 87 4160

[0472] In a cAMP assay using MC1-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 8 exhibited no intrinsic activityat MC1-R and MC4-R, and was a partial agonist at MC5-R.

EXAMPLE 9N-{3-[1-[2(R)-Amino-3-(4-chloro-2-fluoro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0473] The following compound was synthesized by the method of Scheme 3using 2-naphthylacetic acid as J-COOH, D-alaninol asNH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OH as Prt-NH—CH(R₂)—COOH, andBoc-D-4-chloro-2-fluoro-Phe-OH as Q-COOH. It was tested as describedabove with the results shown. The mass was analyzed as 552.9 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 57 82 99 59 Ki (nM) 109 186 6204

[0474] In a cAMP assay using MC1-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 9 was a partial agonist at MC1-Rand MC4-R and an agonist at MC5-R.

EXAMPLE 10N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0475] The following compound was synthesized by the methods of bothSchemes 3 and 5 using 2-naphthylacetic acid as J-COOH, D-alaninol asNH₂—CH(R₅)—CH(R₄)—OH, D-alanine methyl ester as NH₂—CH(R₅)—COOCH₃,Fmoc-L-Arg(Boc)₂—OH as Prt-NH—CH(R₂)—COOH, and Boc-D-2,4-dimethyl-Phe-OHas Q-COOH. It was tested as described above with the results shown. Themass was analyzed as 529.0 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 9 62 100 59 Ki (nM) 1223 15711 717

[0476] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC4-R.

[0477] In rat model IV and ICV penile erection induction experiments atdoses ranging from 0.3 to 30 μg/Kg given IV and at 0.01 to 10 nmolegiven ICV, no penile erection response was observed.

[0478] Feeding studies were conducted as described above ICV at a 1nmole dose level, IV at both 1 and 3 mg/Kg dose levels, and IP(intraperitoneal) at 3 mg/kg. Male Sprague-Dawley (8 to 12 per group)were fed powdered chow and water ad libitum, and dosed ICV, IV or IPwith either vehicle or selected compounds with the following results:Difference in Food Intake vs. Vehicle, Grams of Food ICV IV IV IP 1nmole 1 mg/Kg 3 mg/Kg 3 mg/Kg −4.9 0.9 −6.0 −3.7

[0479] In behavioral satiety studies as in Example 6, the compound ofExample 10 administered IV 2 hours prior to food presentation caused adecrease in food intake and feeding behavior and an earlier onset inresting behavior consistent with a satiety effect, as shown FIG. 2,showing behavior compared to saline, and FIG. 3, showing total one-hourfood intake in grams. No abnormal behavior was seen.

[0480] In conditioned taste avoidance studies, rats or were conditionedto associate a 0.1% saccharin solution with a dose of either lithiumchloride or the compound of Example 10. Two days later, a 0.1% saccharinsolution was presented again. A decrease in fluid intake suggestsdevelopment of a conditioned taste aversion. As shown in FIG. 6, therewas no conditioned taste avoidance associated with the compound ofExample 10.

[0481] Repeat dosing studies were conducted in C57BL/6 mice (n=10 pergroup), housed in a reverse light cycle (on at 12 am off at 12 pm), andweighed daily at 11:00. The compound of Example 6 was diluted in sterilesaline, 0.6 mg/mL and dosed IP at 5 mL/kg at 11:00 am. Mice were dosedwith the compound of Example 10 (3 mg/kg) once per day for 7 days. Asshown in FIG. 8, which also includes data on the compound of Example 6,mice in growth phase administered the compound of Example 10 had asignificant decrease in body weight during the initial 7 days, with agradual increase in body weight, but consistently below control animals,for the two week period following cessation of administration of thecompound of Example 10.

EXAMPLE 11N{3-[1-[2(R)-Amino-3-(2-chloro-4-trifluoromethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0482] The following compound was synthesized by the method of Scheme 3using 2-naphthylacetic acid as J-COOH, D-alaninol asNH₂—CH(R₅)—CH(R₄)—OH, Fmoc-L-Arg(Boc)₂—OH as Prt-NH—CH(R₂)—COOH, andBoc-D-2-chloro-4-trifluoromethyl-Phe-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 549.0(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 0 48 98 52 Ki (nM) 6356 46813 574

[0483] In a cAMP assay using MC4-R, at 1 μM concentrations the compoundof Example 11 exhibited no intrinsic activity.

EXAMPLE 12N-{3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalene-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0484] The following compound was synthesized by both the methods ofboth Schemes 3 and 5 using 2-naphthylacetic acid as J-COOH, D-alanine asNH₂—CH(R₅)—CH(R₄)—OH, D-alanine methyl ester as NH₂—CH(R₅)—COOCH₃,Fmoc-L-Arg(Boc)₂—OH as Prt-NH—CH(R₂)—COOH, and Boc-D-4-chloro-Phe-OH asQ-COOH. It was tested as described above with the results shown. Themass was analyzed as 534.9 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 64 70 97 61 Ki (nM) 94 160 11551

[0485] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MCL-R,MC4-R and MC5-R.

[0486] In ICV feeding studies at 1 nmol dose levels, a 24 hour change infood intake of −3.9 g, and change in weight of −3.9 g, was observed. InIV feed studies at a dose level of 3 mg/Kg, a 24 hour change in foodintake of −9.6, and change in weight of −6.6 g, was observed.

[0487] In rat model IV and ICV penile erection induction experiments atdoses ranging from 0.3 to 30 μg/Kg given IV and at 0.01 to 10 nmolegiven ICV, no penile erection response was observed.

EXAMPLE 13N-{3-[1-[2(R)-Amino-3-(3,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalene-2-yl-ethyl)-piperazin-2(5)-yl]-propyl)-guanidine

[0488] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-3,4-dichloro-Phe-OH as Q-COOH. It wastested as described above with the results shown. The mass was analyzedas 569.3 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 12 37 96 32 Ki (nM) 628 34525 814

[0489] In a cAMP assay using MC1-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 13 exhibited no intrinsicactivity at MC1-R, and was a partial agonist at MC4-R and MC5-R.

EXAMPLE 14N{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-methyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0490] The following compound was synthesized by the method of Scheme 5using 2-naphthoic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2,4-dimethyl-Phe-OH as Q-COOH. It wastested as described above with the results shown. The mass was analyzedas 515.4 (M+H).

Inhibition at 1 μM MC1-R MC3-R MC4-R MC5-R 40 19 66 33

EXAMPLE 15N{3-[1-[4-(4-Chloro-phenyl)-pyrrolidine-3-carbonyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0491] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₄)—COOCH₃, and 1-Boc-4-(4-chlorophenyl)pyrrolidine-3-carboxylicacid as Q-COOH. It was tested as described above with the results shown.The mass was analyzed as 561.4 (M+H).

Inhibition at 1 μM MC1-R MC3-R MC4-R MC5-R 0 39 46 73

EXAMPLE 16 N{1(R)-(4-chloro-2-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-S(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide

[0492] The following compound was synthesized by the method of Scheme 7,in which the compound of Example 45 was treated by the method of Example36 to introduce an acetyl group at the amino group of theD-4-chloro-2-methyl-Phe residue. It was tested as described above withthe results shown. The mass was analyzed as 605.3 (M+H).

Ki (nM) MC1-R MC3-R MC4-R MC5-R 1388 136 5 234

[0493] In a cAMP assay using MC1-R, MC3-R and MC5-R, at 1 μMconcentrations the compound of Example 16 exhibited no intrinsicactivity at MC3-R, and was a partial agonist at MC1-R, MC4-R and MC5-R.

[0494] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg no penile erection response was observed.

EXAMPLE 17N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0495] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 551.7(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 35 83 98 76 Ki (nM) 207 137 6258

EXAMPLE 18N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(3-phenyl-propyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0496] The following compound was synthesized by the method of Scheme 6using hydrocinnamaldhyde as J-aldehyde, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 515.4(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 0 24 69 25 Ki (nM) 670 2652489 650

[0497] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg no penile erection response was observed.

EXAMPLE 19N(3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-p-tolyl-ethyl)-piperazin-2(S)-yl]-propyl)-guanidine

[0498] The following compound was synthesized by the method of Scheme 6using 4-methylphenylacetaldhyde as J-aldehyde, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 515.4(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 32 61 95 65 Ki (nM) 137 16429 448

[0499] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 19 exhibited no intrinsicactivity at MC3-R, and was a partial agonist at MC1-R, MC4-R and MC5-R.

[0500] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg no penile erection response was observed.

EXAMPLE 20N{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-acetyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine

[0501] The following compound was synthesized by the method of Scheme 6using indole-3-acetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 554.4(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 20 35 90 6 Ki (nM) 315 182235 1527

[0502] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 20 exhibited no intrinsicactivity at MC1-R and MC3-R, and was a partial agonist at MC4-R andMC5-R.

[0503] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg no penile erection response was observed.

EXAMPLE 21N-(3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)4-(2-1H-indol-3-yl-propionyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl)-guanidine

[0504] The following compound was synthesized by the method of Scheme 6using indole-3-propionic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 568.5(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 14 34 74 6 Ki (nM) 123 1726323 678

EXAMPLE 22N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-butyryl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine

[0505] The following compound was synthesized by the method of Scheme 6using indole-3-butyric acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 582.6(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 0 32 88 62 Ki (nM) 1203 65790 277

[0506] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg given IV, the compound of Example 22induced 0.5 to 0.8 mean penile erections per rat; on ICV administrationof doses from 0.01 to 10 nmole, no penile erection response wasobserved.

EXAMPLE 23N-(31-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-[2-(1H-indol-3-yl)-ethyl]-5(R)-methyl-piperazin-2(S)-yl}-propyl)-guanidine

[0507] The following compound was synthesized by the method of Scheme 6using indole-3-acetaldehyde as J-aldehyde, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 540.5(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 2 27 93 51 Ki (nM) 257 212237 808

[0508] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 23 exhibited no intrinsicactivity at MC1-R, MC3-R and MC5-R, and was a partial agonist at MC4-R.

EXAMPLE 24N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-[2-(2-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine

[0509] The following compound was synthesized by the method of Scheme 6using 2-methyl-indole-3-acetaldehyde as J-aldehyde, D-alanine methylester as NH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was testedas described above with the results shown. The mass was analyzed as544.5 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 73 57 95 76 Ki (nM) 148 45126 293

[0510] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 24 exhibited no intrinsicactivity at MC3-M, was a partial agonist at MC1-H, and was an agonist atMC4-R and MC5-R.

[0511] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg given IV, the compound of Example 24induced 0.5 mean penile erections per rat; on ICV administration ofdoses from 0.01 to 10 nmole, no penile erection response was observed.

EXAMPLE 25N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-[2-(1-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine

[0512] The following compound was synthesized by the method of Scheme 6using 1-methyl-indole-3-acetaldehyde as J-aldehyde, D-alanine methylester as NH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was testedas described above with the results shown. The mass was analyzed as554.7 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 19 20 74 41 Ki (nM) 2024 76993 1205

EXAMPLE 26N-(31-(2(R)-Amino-(4-chloro-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl-piperazin-2(S)-yl)-propyl)-guanidine

[0513] The following compound was synthesized by the method of Scheme 5using indole-3-acetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-4-chloro-Phe-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 524.5(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 80 60 96 65 Ki (nM) 138 301 8360

[0514] In a CAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 26 exhibited no intrinsicactivity at MC3-R, was a partial agonist at MC1-R and MC5-R, and anagonist at MC4-R.

[0515] In rat ICV feeding studies at 1 nmol dose levels, a 24 hourchange in food intake of −6.0 g, and change in weight of −8.8 g, wasobserved.

[0516] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, no penile erection response was observed.

EXAMPLE 27N-(3-{1-(2(R)-Amino-(4-chloro-2-methyl-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine

[0517] The following compound was synthesized by the method of Scheme 5using indole-3-acetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-4-chloro-2-methyl-Phe-OH as Q-COOH. It wastested as described above with the results shown. The mass was analyzedas 538.6 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 40 74 98 75 Ki (nM) 1730 1775 360

[0518] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 27 exhibited no intrinsicactivity at MC1-R and MC3-R, and was a partial agonist at MC4-R andMC5-R.

[0519] In ICV feeding studies at 1 nmol dose levels, a 24 hour change infood intake of −3.9 g, and change in weight of −4.8 g, was observed.

[0520] In rat model IV and ICV penile erection induction experiments atdoses ranging from 0.3 to 30 μg/Kg given IV and at 0.01 to 10 nmolegiven ICV, no penile erection response was observed.

EXAMPLE 28N-{3-[1-[2(R)-Amino-3-(phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-e&-yl)-piperazin-2(S)-yl]-propyl}-guanidine

[0521] The following compound was synthesized by the methods of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-Phe-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 500.9(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 78 30 86 24 Ki (nM) 26 915119 2141

[0522] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC4-Rand MC5-R.

EXAMPLE 29N-{3-[1-[2(R)-Amino-3-(4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0523] The following compound was synthesized by the method of Schemes 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-4-methyl-Phe-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 515.5(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 50 15 85 33 Ki (nM) 59 503108 884

EXAMPLE 30N-{3-[1-[2(R)-Amino-3-(4-methoxy-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0524] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-4-methoxy]-Phe-OH as Q-COOH. It was testedas described above with the results shown. The mass was analyzed as534.1 (M+H).

Inhibition at 1 μM MC1-R MC3-R MC4-R MC5-R 29 0 61 0

EXAMPLE 31N-{3-[3(4-Chloro-phenyl)-2(R)-dimethylamino-propionyl]-5(R)-methyl-4-(2naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0525] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Fmoc-D-4chloro-Phe-OH as Q-COOH. Methyl groups onthe amino group of D-4-chloro-Phe-OH were attached by a reductiveamination reaction with formaldehyde under the conditions described forsynthesis of 5-3. It was tested as described above with the resultsshown. The mass was analyzed as 563.2 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 55 67 97 38 Ki (nM) 161 174 71019

[0526] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 31 exhibited no intrinsicactivity at MC3-R, was a partial agonist at MC1-R and MC4-R, and anagonist at MC5-R.

EXAMPLE 32N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-methylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0527] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Fmoc-D-4-chloro-Phe-OH as Q-COOH. The methylgroup on the amino group of D-4-chloro-Phe-OH was attached by areductive amination reaction with formaldehyde under the conditionsdescribed in the synthesis of 3-4. It was tested as described above withthe results shown. The mass was analyzed as 549.3 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 63 59 96 22 Ki (nM) 78 212 8863

[0528] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC3-Rand MC4-R, and an agonist as to MC1-R and MC5-R.

EXAMPLE 33N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-diethylamino-propionyl]-5(R)-methyl-4-(2naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0529] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Fmoc-D-4-chloro-Phe-OH as Q-COOH. The ethylgroups on the amino group of D-4-chloro-Phe-OH were attached by areductive amination reaction with acetaldehyde under the conditiondescribed in the synthesis of 3-4. It was tested as described above withthe results shown. The mass was analyzed as 591.3 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 46 29 93 42 Ki (nM) 350 39520 460

[0530] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC1-R,MC3-R and MC4-R, and an agonist as to MC5-R.

EXAMPLE 34N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-isopropylamino-propionyl]-5(R)-methyl-4-(2-naphthalene-2-yl-ethyl)-piperazin-2(5)-yl]-propyl)-guanidine

[0531] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Fmoc-D-4-chloro-Phe-OH as Q-COOH. The iso-propylgroup on the amine group of D-4-chloro-Phe-OH was attached by reductiveamination reaction with acetone under the condition described insynthesis of 3-4. It was tested as described above with the resultsshown. The mass was analyzed as 577.0 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 83 71 98 61 Ki (nM) 12 92 22547

[0532] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC3-R,and an agonist as to MC1-R, MC4-R and MC5-R.

EXAMPLE 35N-{3-[1-[2(R)-Amino-3-naphthalen-2-yl-propionyl]-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guandine

[0533] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-leucinol asNH₂—CH(R₅)—CH(R₄)—OH, D-leucine methyl ester as NH₂—CH(R₅)—COOCH₃, andBoc-D-2-Nal-OH as Q-COOH. It was tested as described above with theresults shown. The mass was analyzed as 593.8 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 6 31 89 48 Ki (nM) 1005 331 3306

[0534] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 35 exhibited no intrinsicactivity at MC1-R, MC3-R and MC4-R, and was a partial agonist at MC5-R.

EXAMPLE 36N-{2-[2(S)-(3-Guanidino-propyl)-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide

[0535] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-leucinol asNH₂—CH(R₅)—CH(R₄)—OH, D-leucine methyl ester as NH₂—CH(R₅)—COOCH₃, andBoc-D-2-Nal-OH as Q-COOH as described in Example 35. An acetyl group wasattached to the amino group of D-2-Nal by reaction of the compound ofExample 35 with Ac-OSu in DMF. It was tested as described above with theresults shown. The mass was analyzed as 635.9 (M+H).

Ki (nM) MC1-R MC3-R MC4-R MC5-R 4616 474 6 378

[0536] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 36 exhibited no intrinsicactivity at MC1-R, MC3-R and MC4-R, and was a partial agonist at MC5-R.

EXAMPLE 37N-{1(R)-(2,4-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide

[0537] The following compound was synthesized by the method of Scheme 5using 2-naphthylacetic acid as J-COOH, D-alaninol asNH₂—CH(R₅)—CH(R₄)—OH, D-alanine methyl ester as NH₂—CH(R₅—COOCH₃, andBoc-D-2,4-dimethyl-Phe-OH as Q-COOH. An acetyl group was attached to theamino group of D-2,4-dimethyl-Phe residue by the method described inExample 36. It was and tested as described above with the results shown.The mass was analyzed as 571.9 (M+H).

Ki (nM) MC1-R MC3-R MC4-R MC5-R 568 74 1 43

[0538] In a cAMP assay using MC4-R, at 1 μM concentrations the compoundof Example 37 exhibited no intrinsic activity.

EXAMPLE 38N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0539] The following compound was synthesized by the method of Scheme 6using 2-naphthylacetic acid as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was tested asdescribed above with the results shown. The mass was analyzed as 565.4(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 43 40 89 50 Ki (nM) 227 59619 548

[0540] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC3-R,and an agonist as to MC1-R, MC4-R and MC5-R.

[0541] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, no penile erection response was observed.

EXAMPLE 39N{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(3H-imidazol-4-ylmethyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine

[0542] The following compound was synthesized by the method of Scheme 6using 4(5)-imidazole carboxyaldehyde as J-aldehyde, D-alanine methylester as NH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was testedas described above with the results shown. The mass was analyzed as477.2 (M+H).

Ki (nM) MC1-R MC3-R MC4-R MC5-R >1000 >1000 >1000 >1000

[0543] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, no penile erection response was observed.

EXAMPLE 40N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(4-imidazol-1-yl-benzyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine

[0544] The following compound was synthesized by the method of Scheme 6using 4-(1H-imidazole-1-yl)benzaldehyde as J-aldehyde, D-alanine methylester as NH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as Q-COOH. It was testedas described above with the results shown. The mass was analyzed as553.2 (M+H).

Ki (nM) MC1-R MC3-R MC4-R MC5-R >1000 >1000 >1000 >1000

EXAMPLE 41N-{2-[2(S)-(3-Guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide

[0545] The following compound was synthesized by the method of Scheme 6.The compound of Example 38 was treated by the method of Example 36 tointroduce an acetyl group at the amino group of the D-2-Nal residue. Itwas tested as described above with the results shown. The mass wasanalyzed as 607.7 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 51 38 97 44 Ki (nM) 625 754 8891

[0546] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC4-R.

[0547] In rat model IV and ICV penile erection induction experiments atdoses ranging from 0.3 to 30 μg/Kg given IV and at 0.01 to 10 nmolegiven ICV, 1 mean penile erection per rat was observed on IVadministration, and no penile erection response was observed on ICVadministration.

EXAMPLE 42N{2-[4-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-l(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-methanesulfonamide

[0548] The following compound was synthesized by the method of Scheme 6using Fmoc-D-2-Nal-OH as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2-Nal-OH as O—COOH. The J-COOH moiety wasfurther modified by removal of the Fmoc group and reacting withmethanesulfonyl chloride to form a sulfonamide moiety. It was tested asdescribed above with the results shown. The mass was analyzed as 672.4(M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 55 77 100 66 Ki (nM) 97 205 7151

[0549] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 42 exhibited no intrinsicactivity at MC3-R, was a partial agonist at MC1-R, and an agonist atMC4-R and MC5-R.

[0550] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, no penile erection response was observed.

EXAMPLE 43N-{2-[4-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamideThe following compound was synthesized by the method of Scheme 6 usingFmoc-D-2-Nal-OH as J-COOH, D-alanine methyl ester as NH₂—CH(R₅)—COOCH₃,and Boc-D-2-Nal-OH as O—COOH. The J-COOH moiety was further modified byremoval of the Fmoc group and reacting with acetic anhydride to form aacetamide moiety. It was tested as described above with the resultsshown. The mass was analyzed as 636.3 (M+H).

[0551]

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 27 69 95 61 Ki (nM) 430 15711 291

[0552] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 43 exhibited no intrinsicactivity at MC3-R, was a partial agonist at MC1-R and was an agonist atMC4-R and MC5-R.

[0553] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, no penile erection response was observed.

EXAMPLE 44N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0554] The following compound was synthesized by the method of Scheme 7using 2-naphthyl acetic acid as J-COOH, L-Orn(Boc) methyl ester asNH₂—CH(R₂)—COOCH₃, and Boc-D-2,4-di-methyl-Phe-OH as O—COOH. It wastested as described above with the results shown. The mass was analyzedas 543.4 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 0 25 86 7 Ki (nM) 431 526 61536

[0555] In a cAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC1-R,MC3-R and MC5-R, and an agonist as to MC4-R.

[0556] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, 0.5 to 0.7 mean penile erections per ratwere observed.

EXAMPLE 45N-{3-[1-[2(R)-Amino-3-(4-chloro-2-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0557] The following compound was synthesized by the method of Scheme 7using 2-naphthyl acetic acid as J-COOH, L-Orn(Boc) methyl ester asNH₂—CH(R₂)—COOCH₃, and Boc-D-4-chloro-2-methyl-Phe-OH as Q-COOH. It wastested as described above with the results shown. The mass was analyzedas 543.4 (M+H).

MC1-R MC3-R MC4-R MC5-R Inhibition at 1 μM 3 34 96 36 Ki (nM) 462 398 3774

[0558] In a CAMP assay for determination of agonist/antagonist status,it was determined that the compound was a partial agonist as to MC1-Rand MC3-R, and an agonist as to MC4-R and MC5-R.

[0559] In rat model IV penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, 0.5 to 0.7 mean penile erections per ratwere observed.

EXAMPLE 46 N-{1(R)-(2,4-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide

[0560] The following compound was synthesized by the method of Scheme 7.The compound of Example 44 was treated with the method of Example 36 tointroduce an acetyl group at the amino group of D-2,4-dimethyl-Phe. Itwas tested as described above with the results shown. The mass wasanalyzed as 585.4 (M+H).

Ki (nM) MC1-R MC3-R MC4-R MC5-R 1883 232 11 250

[0561] In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 μMconcentrations the compound of Example 46 exhibited no intrinsicactivity at MC1-R, MC3-R and MC5-R, and was a partial agonist at MC4-R.

[0562] In rat model penile erection induction experiments at dosesranging from 0.3 to 30 μg/Kg, no penile erection response was observed.Example 472(S)-Amino-N-{1(R)-(2,4-dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acethyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamideThe following compound was synthesized by the method of Scheme 7, whereafter introduction of the 2,4 dimethyl-Phe derivative to the compound, aHis derivative was attached at the N-terminus by methods similar tothose described for the conversion of 5-7 to 5-8. It was tested asdescribed above with the results shown. The mass was analyzed as 680.3(M+H).

Inhibition at 1 μM MC1-R MC3-R MC4-R MC5-R 93 72 97 50

EXAMPLE 48N{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-3(S)-yl]-propyl}-guanidine

[0563] The following compound was synthesized by the method of Scheme 7using 2-naphthyl acetic acid as Q-COOH, L-Orn(Boc) methyl ester asNH₂—CH(R₂)—COOCH₃, and Boc-D-2,4-di-methyl-Phe-OH as J-COOH. It wastested as described above with the results shown. The mass was analyzedas 543.2 (M+H).

Inhibition at 1 μM MC1-R MC3-R MC4-R MC5-R 12 26 26 72

EXAMPLE 49N-[2-[4-[2(R)-Acetylamino-3-(4-chloro-phenyl)-propionyl]-2(S),5(S)-bis-(3-guanidino-propyl)-piperazin-1-yl]-1(R)-(4-chloro-benzyl)-2-oxo-ethyl]-acetamide

[0564] The following compound is synthesized by the method of Scheme 9using D-4-Cl-Phe as Q-COOH, and an acetyl group is attached to the aminogroup of D-4-Cl-Phe by conventional means, such as reaction of thecompound with Ac-OSu in DMF.

EXAMPLE 50N-{3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine

[0565] The compound is synthesized by the method of Scheme 10 using2-naphthyl acetic acid as J-COOH that is reacted with an aminopropanolderivative to obtain 10-1. D-4-Cl-Phe is employed as Q-COOH.

EXAMPLE 51N-(3-{1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-3-oxo-4-phenethyl-piperazin-2(S)-yl}-propyl)-guanidine

[0566] The following compound is synthesized by the method of Example 48using phenyl acetic acid as J-COOH.

EXAMPLE 52N-(31-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]4-[2-(1H-indol-3-yl)-ethyl]-5(R)-methyl-3-oxo-piperazin-2(S)-yl}-propyl)-guanidine

[0567] The following compound is synthesized by the method of Example 48using 3-indole acetic acid as J-COOH.

EXAMPLE 53N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2yl-ethyl-oxo-piperazin-2(S)-yl-propyl)-guanidine

[0568] The following compound is synthesized by the method of Example 48using 2-Nal amino acid as Q-COOH.

EXAMPLE 54 2(S)-Amino-N-{1(R)-(4-chloro-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-2-oxo-ethyl)-3-(1H-imidazol-4-yl)-propionamide

[0569] The following compound is synthesized by the method of Example 48where after introduction of D-4-Cl-Phe to the compound, a His derivativeis attached at the N-terminus by methods similar to those described forthe conversion of 10-4 to 10-5.

EXAMPLE 552(S)-Amino-N-(1(R)-(2,4-dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamide

[0570] The following compound is synthesized by the method of Scheme 5where after introduction of D-2,4 dimethyl-Phe to the compound, a Hisderivative is attached at the N-terminus by methods similar to thosedescribed for the conversion of 5-7 to 5-8.

EXAMPLE 56N{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine

[0571] The following compound is synthesized by the method of example 48where after introduction of D-4-chloro-Phe to the compound, apolyethylene glycol (FW 100-10000) carboxylic acid derivative isattached at the N-terminus by methods similar to those described for theconversion of 10-4 to 10-5.

EXAMPLE 57N-(3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-piperazin-2(S)-yl]-propyl}-guanidine

[0572] The following compound is synthesized by the method of Scheme 5where after introduction of D-4-Chloro-Phe to the compound, apolyethylene glycol (FW 100-10000) carboxylic acid derivative isattached at the N-terminus by methods similar to those described for theconversion of 5-7 to 5-8.

EXAMPLE 58N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R),6(R)-dimethyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0573] The following compound is synthesized by the methods of Scheme 3and 4 where J-COOH is 2-naphthyl acetic acid and Q-COOH isD-2,4-dichoro-Phe.

EXAMPLE 59N-{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-piperazin-2(S)-yl]-propyl}-guanidine

[0574] The following compound is synthesized by the method of Scheme 5,wherein after introduction of D-4-chloro-Phe to the compound, apolyethylene glycol (FW 100-10000) carboxylic acid derivative isattached at the N-terminus by methods similar to those described for theconversion of 5-7 to 5-8.

EXAMPLE 60N-{2-[4-(2(R)-Amino-3-(2,4-dimethyl-phenyl)-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-benzyl-2-oxo-ethyl}-acetamide

[0575] The following compound 1a synthesized by the method of Scheme 6using Fmoc-D-Phe-OH as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2,4-dimethyl-Phe-OH as Q-COOH. The J-COOHmoiety is further modified by removal of the Fmoc group and reactingwith acetic anhydride to form an acetamide moiety.

EXAMPLE 61N-(2-[4-(2(R)-Amino-3-(2,4-dimethyl-phenyl)-2-yl-propionyl)-S(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-(3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-2-oxo-ethyl]-acetamide

[0576] The following compound is synthesized by the method of Scheme 6using Fmoc-D-Trp(Boc)-OH as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and Boc-D-2,4-dimethyl-Phe-OH as Q-COOH. The J-COOHmoiety is further modified by removal of the Fmoc group and reactingwith acetic anhydride to form an acetamide moiety.

EXAMPLE 62N-{1l(R)-Benzyl-2-[4-[3-(2,4-dichloro-phenyl)-propionyl]-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-2-oxo-ethyl}-acetamide

[0577] The following compound is synthesized by the method of Scheme 6using Fmoc-D-Phe-OH as J-COOH, D-alanine methyl ester asNH₂—CH(R₅)—COOCH₃, and 3-(2,4-dichlorophenyl)-propionic acid as Q-COOH.The J-COOH moiety is further modified by removal of the Fmoc group andreacting with acetic anhydride to form anacetamide moiety.

EXAMPLE 63N-3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine

[0578] The following compound is synthesized by the method of Scheme 7using phenylacetic acid as J-COOH, and Boc-D-4-chloro-2-methyl-Phe-OH asQ-COOH.

EXAMPLE 64N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl}-propyl)-guanidine

[0579] The following compound is synthesized by the method of Scheme 7using 3-phenylpropionic acid as J-COOH, andBoc-D-4-chloro-2-methyl-Phe-OH as Q-COOH.

EXAMPLE 65N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(4-phenyl-butyryl)-piperazin-2(S)-yl}-propyl)-guanidine

[0580] The following compound is synthesized by the method of Scheme 7using 4-phenylbutyric acid as J-COOH, and Boc-D-4-chloro-2-methyl-Phe-OHas Q-COOH.

EXAMPLE 66N-(3-{1-[3-(2,4-Dichloro-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine

[0581] The following compound is synthesized by the method of Scheme 7using phenylacetic acid as J-COOH and 3-(2,4-dichloro-phenyl)-propionicacid as Q-COOH.

EXAMPLE 67N{3-[1-(2(R)-Amino-2-phenyl-acetyl)-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0582] The following compound is synthesized by the method of Scheme 7using 3-phenylpropionic acid as J-COOH and Boc-D-phenylglycine asQ-COOH.

EXAMPLE 68N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-isobutyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine

[0583] The following compound is synthesized by the method of Scheme 7using 2-Naphtylacetic acid as J-COOH, Fmoc-D-Leucine asFmoc-NH—CH(R₅)—OH and Boc-D-2-Nal-OH as Q-COOH.

[0584] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0585] Although the invention has been described in detail withparticular reference to these preferred embodiments, other embodimentscan achieve the same results. Variations and modifications of thepresent invention will be obvious to those skilled in the art and it isintended to cover in the appended claims all such modifications andequivalents. The entire disclosures of all references, applications,patents, and publications cited above are hereby incorporated byreference.

What is claimed is:
 1. A compound having the formula of structure l:

or an enantiomer, stereoisomer or diastereoisomer thereof, or apharmaceutically acceptable salt thereof, wherein X is CH₂, C═O or C═S;R₁ is -L₁-J; One of R_(2a) and R_(2b) is -L₂—W and the remaining ofR_(2a) and R_(2b) is hydrogen; R₃ is -L₃-Q; L₁ is a bond or a linkerunit comprising from one to eight backbone atoms selected from the groupconsisting of carbon, sulfur, oxygen or nitrogen; J is a ring structureselected from the group consisting of substituted or unsubstitutedaromatic carbocyclic rings, substituted or unsubstituted non-aromaticcarbocyclic rings, substituted or unsubstituted aromatic fusedcarbobicyclic ring groups, two substituted or unsubstituted aromaticcarbocyclic rings wherein the rings are joined by a bond or —O—, andsubstituted or unsubstituted aromatic fused heterobicyclic ring groups;wherein in each instance the rings include 5 or 6 ring atoms; L₂ is abond or —(CH₂)_(y)—; W is a heteroatom unit with at least one cationiccenter, hydrogen bond donor or hydrogen bond acceptor wherein at leastone heteroatom is nitrogen or oxygen; L₃ is a bond or a linker unitcomprising from one to nine backbone atoms selected from the groupconsisting of carbon, sulfur, oxygen or oxygen or nitrogen; Q is anaromatic carbocyclic ring selected from the group consisting of phenyl,substituted phenyl, naphthyl and substituted naphthyl; One or two ofR_(4a), R_(4b), R_(5a), and R_(5b) are independently -L₂—W or a C₁ to C₆aliphatic linear or branched chain and the remaining of R_(4a), R_(4b),R_(5a), and R_(5b) are hydrogen, provided that at least one of R_(4a)and R_(4b) and at least one of R_(5a) and R_(5b) are hydrogen; and y isat each occurrence independently from 1 to
 6. 2. The compound of claim 1wherein X is CH₂.
 3. The compound of claim 1 wherein L₁ is a linker unitselected from the group consisting of: —(CH₂)_(y)—, —(CH₂)_(y)O,—(CH₂)_(y)C(═O)—, —(CH₂)_(y)—NH—, —(CH₂)_(y)—NH—C(═O)—,—(CH₂)_(y)—C(═O)—NH—, —(CH₂)_(y)C(═O)—O—, —(CH₂)_(y)S—,—(CH₂)_(y)—SO₂—NH—, —NH—C(═O)—, —NH—C(═O)-(CH₂)_(y)—,—NH—SO₂—(CH₂)_(y)—, —NH—(CH₂)_(y)—, —NH—(CH₂)_(y)—O—, —SO₂—(CH₂)_(y)—,—C(═O)—NH—, —C(—O)—NH—(CH₂)_(y)—, —C(═O)-(CH₂)_(y)—, —C(═O)— and—C(═O)—O—(CH₂)_(y)—; where y is from 1 to
 6. 4. The compound of claim 1wherein J is a substituted or unsubstituted ring structure selected fromthe group consisting of


5. The compound of claim 4 wherein J is substituted with one or morering substituents independently selected from the group consisting ofhydroxyl, halogen, sulfonamide, alkyl or aryl groups attached directlyor through an ether linkage.
 6. The compound of claim 1 where L₂ is(CH₂)_(y) wherein y is between 1 and
 4. 7. The compound of claim 1wherein W is a heteroatom unit with at least one cationic centerselected from the group consisting of —NH₂ and —NH—C(═NH)—NH₂.
 8. Thecompound of claim 1 wherein W is a heteroatom unit with at least onecationic center, hydrogen bond donor or hydrogen bond acceptor selectedfrom the group consisting of: —NH—C(═O)—CH₃, —C(═O)—NH—CH₃,—NH—C(═NH)—NH—CH₃, —NH—C(═NH)—NH—CH₂—CH₃, —NH—C(═NH)—NH—CH₂—CH₂—CH₃,—NH—C(═NH)—NH₂, —NH—C(═O)—O—CH₃, —NH—C(═O)—CH₃, —NH—C(═O)—NH₂,—NH—C(═O)—NH—CH₃, —NH—SO₂—NH₂, —NH—SO₂—CH₃, —C(═O)—NH₂, —OH,


9. The compound of claim 1 wherein L₃ is a linker unit selected from thegroup consisting of: —(CH₂)_(y)—, —(CH₂)_(y)—O—, —(CH₂)_(y)OC(═O)—,—(CH₂)_(y)—N(R_(6a),R_(6b)), —(CH₂)_(y)NR_(6a)—C(═O)—,—(CH₂)_(y)CH(NR_(6a)R_(6b))-(CH₂)_(y)—,—(CH₂)_(y)C(═O)CH(NR_(6a)R_(6b))(CH₂)_(y)—, —(CH₂)_(y)C(═O)—(CH₂)_(y)—C(═O)—NH—, —(CH₂)_(y)—CH(CH₃)—O—, —(CH₂)_(y)—CH(CH₃)—C(═O)—,—(CH₂)_(y)C(═O)—O—, —CH₂)_(y)—C(═O)—S—, —(CH₂)_(y)S, —(CH₂)_(y)—S—S—,—(CH₂)_(y)—SO₂—NH—, —NH—C(═O)—, —NH—C(═O)-(CH₂)_(y)—,—NH—SO₂—(CH₂)_(y)—, —NH—(CH₂)_(y)—, —NH—(CH₂)_(y)—O—, —NH—(CH₂)_(y)—NH—,—NH—(CH₂)_(y)—NH—C(═O)—, —NH—(CH₂)_(y)—C(═O)—NH—, —NH—(CH₂)_(y)—S—,—NH—(CH₂)_(y)—S—S, —NH—(CH₂)_(y)—C(═O)—, —SO₂—(CH₂)_(y)—,—C(═O)-(CH₂)_(y)—C(═O)—, —C(═O)-(CH₂)_(y)C(═O)NH,—C(═O)-(CH₂)_(y)—NH—C(═O)—, —C(═O)—NH—, —C(═O)—NH—(CH₂)_(y)—,—C(═O)CH(NR_(6a),R_(6b))(CH₂)_(y)—, —C(═O)-(CH₂)_(y)—O—,—C(═O)—CH(CH₃)—O—, —C(═O)—CH(CH₃)—NH—, —C(═O)—CH(CH₃)—NH—C(═O)—,—C(═O)-(CH₂)_(y)—, —C(═O)-(CH₂)_(y)—CH(NR_(6a),R_(6b))—,—C(═O)-(CH₂)_(y)—CH(NR_(6a),R_(6b))-(CH₂)_(y)—,—C(═O)-(CH₂)_(y)—CH(NHR_(6a),R_(6b))—C(═O)—, —C(═O)-(CH₂)_(y)—S—,—C(═O)-(CH₂)_(y)—S—S—, —C(═O)—, —C(═O)—O—(CH₂)_(y)—,

wherein R_(6a) and R_(6b) are each independently selected from the groupconsisting of hydrogen, R₇ and R₇—R₈; R₇ is an amino acid residue or anamine capping group, provided that if R₈ is present, R₇ is an amino acidresidue; R₈ is H or an amine capping group; and y is from 1 to 6,provided that where any linker unit includes two y index values, thetotal of such y index values is from 2 to
 6. 10. The compound of claim 9wherein the amino acid residue is an L-amino acid selected from thegroup consisting of Abu, 2-Abz, 3-Abz, 4-Abz, Achc, Acpc, Aib, Amb,Arg(Tos), Asp(anilino), Asp(3-Cl-anilino), Asp(3,5-diCl-anilino),11-Aun, AVA, Beta-hHyp(Bzl), Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA,GBzA, B-Gpa, GVA(CI), His, hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp,2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip, 4-phenylPro, 5-phenylPro, Pyr,Sar, Tle, Tiq, Atc, Igl, Hyp(2-Naphthyl), Hyp(Phenyl), 2-Aic, Idc,1-Aic, Beta-homoSer(Bzl), Ser(2-Naphthyl), Ser(Phenyl),Ser(4-Cl-Phenyl), Ser(2-Cl-Phenyl), Thr(Bzl), Tic, Beta-homoThr(Bzl),Thr(2-Naphthyl), Thr(Phenyl), Thr(4-Cl-Phenyl) and Thr(2-Cl-Phenyl),Nle, Leu, lie, Val and Beta-Ala.
 11. The compound of claim 9 wherein theamine capping group is selected from the group consisting of methyl,dimethyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, allyl,cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl,phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl,benzyl, benzoyl, 12-Ado, 7′-amino heptanoyl, 6-Ahx, Amc and 8-Aoc. 12.The compound of claim 9 wherein the amine capping group is polyethyleneglycol with a formula molecular weight of between 100 and 10,000. 13.The compound of claim 1 wherein Q is

wherein R_(9a) and R_(9b) are optional ring substituents, and when oneor both are present, are the same or different and independentlyhydroxyl, halogen, alkyl, or aryl groups attached directly or through anether linkage.
 14. The compound of claim 13 wherein at least one ofR_(9a) or R_(9b) is an alkyl selected from the group consisting of —CH₃and —OCH₃.
 15. The compound of claim 13 wherein at least one of R_(9a)or R_(9b) is a halogen selected from the group consisting of —Cl and—CF₃.
 16. The compound of claim 1 wherein one of R_(4a), R_(4b), R_(5a),and R_(5b) is a C₁ to C₆ aliphatic linear or branched chain.
 17. Thecompound of claim 1 wherein one of R_(4a) or R_(4b) and one of R_(5a)and R_(5b) is a C₁ to C₆ aliphatic linear or branched chain.
 18. Thecompound of claim 16 wherein the C₁ to C₆ aliphatic linear or branchedchain is selected from the group consisting of methyl and isobutyl. 19.The compound of claim 1 wherein X is CH₂; L₁ is a linker unit selectedfrom the group consisting of —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —C(═O)—CH₂—,—C(═O)-(CH₂)₂— and —C(═O)-(CH₂)₃—; J a ring structure selected from thegroup consisting of naphthyl, phenyl, substituted phenyl, indole andsubstituted indole; L₂ is (CH₂)₃; W is —NH—C(═NH)—NH₂; L₃ is a linkerunit selected from the group consisting ofC(═O)(C—NR_(6a)R_(6b))(CH₂)_(y)—, —C(═O)-(CH₂)_(y)— and—(CH₂)_(y)—(C—NR_(6a)R_(6b))-(CH₂)_(y)—; Q is an aromatic carbocyclicring selected from the group consisting of phenyl, substituted phenyland naphthyl; One of R_(4a), R_(4b), R_(5a), and R_(5b) is methyl orisobutyl, and the remaining of R_(4a), R_(4b), R_(5a), and R_(5b) arehydrogen; R_(6a) and R_(6b) are each independently selected from thegroup consisting of hydrogen and R₇; and R₇ is selected from the groupconsisting of acetyl, methyl, dimethyl, ethyl, propyl, isopropyl, butyl,isobutyl, benzyl, benzoyl, hexanoyl, and polyethylene glycol.
 20. Thecompound of claim 1 and pharmaceutically acceptable salts thereofselected from the group consisting of:N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-6(S)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2-chloro-4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(S)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(4-chloro-2-fluoro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2-chloro-4-trifluoromethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(3,4-dichloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-1-naphthalene-2-yl-methyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[4-(4-Chloro-phenyl)-pyrrolidine-3-carbonyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{1(R)-(4-chloro-2-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(3-phenyl-propyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-(2(R)-Amino-3-naphthalen-2-y-propionyl)-5(R)-methyl-4-(2-p-tolyl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-acetyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-propionyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(2-1H-indol-3-yl-butyryl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-[2-(1H-indol-3-yl)-ethyl]-5(R)-methyl-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-[2-(2-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-[2-(1-methyl-1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-(2(R)-Amino-(4-chloro-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-(2(R)-Amino-(4-chloro-2-methyl-phenyl)-propionyl)-5(R)-methyl-4-[2-(1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl}-propyl)-guanidine;N-{3-[1-[2(R)-Amino-3-(phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(4-methyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(4-methoxy-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-dimethylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-methylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-diethylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[3-(4-Chloro-phenyl)-2(R)-isopropylamino-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-naphthalen-2-yl-propionyl]-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{2-[2(S)-(3-Guanidino-propyl)-5(R)-isobutyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;N-{1(R)-(2,4-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidineN-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(3H-imidazol-4-ylmethyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(4-imidazol-1-yl-benzyl)-5(R)-methyl-piperazin-2(S)-yl]-propyl}-guanidine;N-{2-[2(S)-(3-Guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;N-{2-[4-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R₁)-naphthalen-2-ylmethyl-2-oxo-ethyl}-methanesulfonamide;N-{2-[4-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-naphthalen-2-ylmethyl-2-oxo-ethyl}-acetamide;N-{3-[1-[²(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(4-chloro-2-dimethyl-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{1(R)(2,4-Dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-acetamide;2(S)-Amino-N-{1(R)-(2,4-dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-acethyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamideN-{3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-3(S)-yl]-propyl}-guanidineN-[2-[4-[2(R)-Acetylamino-3-(4-chloro-phenyl)-propionyl]-2(S),5(S)-bis-(3-guanidino-propyl)-piperazin-1-yl]-1(R)-(4-chloro-benzyl)-2-oxo-ethyl]-acetamide;N-{3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine;N-(3-{1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-3-oxo-4-phenethyl-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-4-[2-(1H-indol-3-yl)-ethyl]-5(R)-methyl-3-oxo-piperazin-2(S)-yl}-propyl)-guanidine;N-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine;2(S)-Amino-N-{1(R)-(4-chloro-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamide;2(S)-Amino-N-{1(R)-(2,4-dimethyl-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(1H-imidazol-4-yl)-propionamide;N-{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R),6(R)-dimethyl-4-(2-naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl}-guanidine;N-{3-[1-[2(R)-(PEG-Amino)-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2-naphthalen-2-yl-ethyl)-3-piperazin-2(S)-yl]-propyl}-guanidine;N-{2-[4-(2(R)-Amino-3-(2,4-dimethyl-phenyl)-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-benzyl-2-oxo-ethyl}-acetamide;N-{2-[4-(2(R)-Amino-3-(2,4-dimethyl-phenyl)-2-yl-propionyl)-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-1(R)-(3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-2-oxo-ethyl}-acetamide;N-{1(R)-Benzyl-2-[4-[3-(2,4-dichloro-phenyl)-propionyl]-5(S)-(3-guanidino-propyl)-2(R)-methyl-piperazin-1-yl]-2-oxo-ethyl}-acetamide;N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-[2(R)-Amino-3-(4-chloro-2-methyl-phenyl)-propionyl]-5(R)-methyl-4-(4-phenyl-butyryl)-piperazin-2(S)-yl}-propyl)-guanidine;N-(3-{1-[3-(2,4-Dichloro-phenyl)-propionyl]-5(R)-methyl-4-phenylacetyl-piperazin-2(S)-yl}-propyl)-guanidine;N-{3-[1-(2(R)-Amino-2-phenyl-acetyl)-5(R)-methyl-4-(3-phenyl-propionyl)-piperazin-2(S)-yl]-propyl}-guanidine;andN-{3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-isobutyl-4-(2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl}-guanidine.21. The compound of claim 1 of the formula of structure II:

wherein R₁₀ is H or ═O; Z is N, NH, CH, CH₂ or N—CH₃; R₁₁, R₁₂, R₁₃ andR₁₄ are independently hydrogen or a C₁ to C₆ linear or branched chain onthe proviso that either R₁₁ and R₁₂, or, if n is 1, R₁₂ and R₁₃, canconstitute an aromatic or non-aromatic carbocyclic ring; R₁₅, R₁₆, andR₁₉ are independently hydrogen or a hydroxyl, halogen, alkyl or arylgroups attached directly or through an ether linkage; R₁₇ and R₁₈ areindependently hydrogen, a hydroxyl, halogen, alkyl or aryl groupsattached directly or through an ether linkage, or together constitute afused aromatic ring; R₂₀ is hydrogen or a C₁ to C₆ aliphatic linear orbranched chain, optionally containing at least one N; R₂₁ is optionallynot present, or if present is a C₁ to C₆ aliphatic linear or branchedchain; R_(22a) and R_(22b) are independently hydrogen or a C₁ to C₆linear or branched chain on the proviso that R₂₀ and one of R_(22a) andR_(22b) can form a nonaromatic heterocyclic ring; m is from 0 to 6; n is0 or 1; and the dashed lines are an optional double bond.
 22. Thecompound of claim 1 wherein one of R_(5a) and R_(5b) is an(R)-configuration C₁, to C₆ aliphatic linear or branched chain and theremaining of R_(4a), R_(4b), R_(5b) are hydrogen.
 23. The compound ofclaim 19 wherein one of R_(5a) and R_(5b) is (R)-methyl or (R)-isobutyland the remaining of R_(4a), R_(4b), R_(5a), and R_(5b) are hydrogen.24. The compound of claim 22 wherein L₁ is a linker unit selected fromthe group consisting of —CH₂—, —(CH₂)₂— and —(CH₂)₃—.
 25. The compoundas in any of claims 22, 23 or 24 wherein the compound binds to themelanocortin 4 receptor with high affinity and exhibits no intrinsicactivity at the melanocortin 4 receptor.
 26. A pharmaceuticalcomposition, comprising a compound of any one of claim 22, 23 or 24 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 27. A method of treating obesity or feeding-relateddisorders, comprising administration of a therapeutically effectiveamount of a pharmaceutical composition of claim
 26. 28. The compound ofclaim 1 wherein one of R_(5a) and R_(5b) is an (R)-configuration C₁, toC₆ aliphatic linear or branched chain and the remaining of R_(4a),R_(4b), R_(5a), and R_(5b) are hydrogen and wherein L₁ is selected fromthe group consisting of —C(═O)—CH₂—, —C(═O)-(CH₂)₂— and —C(═O)-(CH₂)₃—.29. The compound of claim 19 wherein one of R_(5a) and R_(5b) is(R)-methyl or (R)-isobutyl and the remaining of R_(4a), R_(4b), R_(5a),and R_(5b) are hydrogen and wherein L₁ is selected from the groupconsisting of —C(═O)—CH₂—, —C(═O)-(CH₂)₂— and —C(═O)-(CH₂)₃—.
 30. Thecompound as in any of claims 28 or 29 wherein the compound is an agonistor partial agonist at the melanocortin 4 receptor.
 31. A method oftreating obesity or feeding-related disorders, comprising administrationof a therapeutically effective amount of a compound of any of claims 1,19 or 21 wherein the compound binds to the melanocortin 4 receptor withhigh affinity and exhibits no intrinsic activity at the melanocortin 4receptor.